Aryl-substituted heterocycles, process for their preparation and their use as medicaments

ABSTRACT

The invention relates to substituted aryl-substituted heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof, to process for their preparation and to their use as medicaments. 
     Compounds of the Formula I 
                         
in which the radicals have the stated meanings, the N-oxides thereof, and the physiologically tolerated salts thereof, and process for the preparation thereof are described. The compounds bring about for example a weight reduction in mammals and are suitable for example for the prevention and treatment of obesity and diabetes.

The invention relates to aryl-substituted heterocycles and to thephysiologically tolerated salts and physiologically functionalderivatives thereof.

Compounds similar in their overall structure to the heterocyclesdescribed herein and having a pharmacological effect have been describedin the prior art. Thus, for example, WO 03/097047 describesaryl-substituted oxadiazoles for the treatment of obesity and diabetes.

Compounds with MCH-antagonistic activity for treatment of obesity aredisclosed in the prior art (examples: WO2001021577, WO2003035624,WO2002089729, WO2002006245, WO2002002744, WO2002057233, WO2003045313,WO2003097047, WO2002010146, WO2003087044).

The invention was based on the object of providing compounds which bringabout a weight reduction in mammals and are suitable for the preventionand treatment of obesity and diabetes.

Surprisingly, a series of compounds which modulate the activity of MCHreceptors has been found. In particular, the compounds are distinguishedby MCH1R antagonism.

The invention therefore relates to compounds of the formula I,

in which the meanings are

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,    —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(n)—R12,    CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(s)O(R21); or R1 and    R2 form together with the nitrogen atom to which they are bonded a 4    to 10-membered mono-, bi- or spirocyclic ring which, apart from the    nitrogen atom, may include 0 to 4 additional heteroatoms selected    from the group of oxygen, nitrogen and sulfur, where the    heterocyclic ring system may additionally be substituted by F, Cl,    Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,    (C₀-C₈)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy,    COO(R25), N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28) or SO₂CH₃;-   o 0, 1, 2, 3, 4, 5, 6;-   q, s independently of one another 0, 1, 2, 3, 4;-   R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28    independently of one another H, (C₁-C₆)-alkyl;-   R17 and R18, R23 and R24, R27 and R28 independently of one another    optionally together with the nitrogen atom to which they are bonded    a 5-6 membered ring which, apart from the nitrogen atom, may also    include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur;-   R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33),    3-12 membered mono-, bi- or spirocyclic ring which may comprise one    or more heteroatoms from the group of N, O and S, and the 3-12    membered ring may comprise further substituents such as F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl,    O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),    CO(C₁-C₆)-alkyl, COO(R36) and S(O)_(u)(R37);-   u 0, 1, 2;-   R34, R35 independently of one another H, (C₁-C₈)-alkyl;-   R34 and R35 optionally together with the nitrogen atom to which they    are bonded a 5-6 membered ring which, apart from the nitrogen atom,    may also include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur, and optionally be substituted by    1-2 oxo groups;-   R36, R37 H, (C₁-C₈)-alkyl;-   R13, R14 independently of one another H, (C₁-C₈)-alkyl,    hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;-   R29, R30, R31 independently of one another H, (C₁-C₈)-alkyl,    (C₂-C₆)-alkenyl, (C₀-C₈)-alkylene-aryl;-   R32, R33 independently of one another H, (C₁-C₆)-alkyl or-   R32 and R33 optionally together with the nitrogen atom to which they    are bonded a 5-6 membered ring which, apart from the nitrogen atom,    may also include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur and optionally be substituted by    1-2 oxo groups;-   R3 H, (C₁-C₆)-alkyl;-   R4, R5 independently of one another H, (C₁-C₆)-alkyl, OH,    O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl;    -   R6, R7, R8, R9 independently of one another H, (C₁-C₈)-alkyl, or-   R6 and R7, R8 and R9 independently of one another optionally oxo;-   n, m independently of one another 0, 1, 2;-   A, B, D, G independently of one another N, C(R38);-   R38 H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,    O(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,    (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R39)(R40),    SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R41)(R42), N(R43)CO(R44),    N(R45)SO₂(R46), CO(R47), —(CR48R49)_(x)—O(R50);-   R39, R40, R41, R42, R43, R45 independently of one another H,    (C₁-C₈)-alkyl; or-   R39 and R40, R41 and R42 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur;-   R44, R46, R47 independently of one another H, (C₁-C₈)-alkyl, aryl;-   R48, R49 independently of one another H, (C₁-C₈)-alkyl;-   R50 H, (C₁-C₆)-alkyl;-   x 1, 2, 3, 4;-   Het five-membered aromatic heterocycle-   X a bond, a group of the formula —(CR51R52)_(y)-in which one or more    —(CR51R52)-groups may be replaced by Y to result in a chemically    reasonable radical, C═C, C≡C;-   Y O, S, N(R53), CO, SO, SO₂;-   R51, R52 independently of one another H, (C₁-C₄)-alkyl, where R51    and R52 in the y groups may in each case have the same or different    meanings;-   y 1, 2, 3, 4, 5, 6;-   R53 H, (C₁-C₈)-alkyl;-   E 3-14 membered bivalent carbo- or heterocyclic ring structure    having 0-4 heteroatoms from the group of N, O and S, which may    optionally have substituents from the group of H, F, Cl, Br, I, OH,    CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl,    S-aryl, N(R54)(R55), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl,    CON(R56)(R57), N(R58)CO(R59), N(R60)SO₂(R61), CO(R62) and be mono-    or bicyclic;-   R54, R55, R56, R57, R58, R60 independently of one another H,    (C₁-C₈)-alkyl;-   R54 and R55, R56 and R57 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur;-   R59, R61, R62 independently of one another H, (C₁-C₈)-alkyl, aryl;-   K a bond, a group of the formula —(CR63R64)_(z)-in which one or more    —(CR63R64)-groups may be replaced by Z to result in a chemically    reasonable radical, C≡C, C═C;-   Z O, S, N(R65), CO, SO, SO₂;-   R63, R64 independently of one another H, (C₁-C₈)-alkyl, hydroxy,    (C₁-C₆)-alkoxy, where R63 and R64 in the z groups may in each case    have the same or different meanings;-   z 1, 2, 3, 4, 5, 6; preferably 2, 3, 4, 5, 6;-   R65 H, (C₁-C₈)-alkyl;-   R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring    which may include 0 to 4 heteroatoms selected from the group of    oxygen, nitrogen and sulfur, where the ring system may additionally    be substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl,    O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    (C₀-C₈)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68), hydroxy,    hydroxy-(C₁-C₄)-alkyl, COO(R69), N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72)    or SO₂CH₃;-   R66, R67, R68, R69, R70, R71, R72 independently of one another H,    (C₁-C₈)-alkyl; or-   R67 and R68, R71 and R72 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur; or    the N-oxides thereof and the physiologically tolerated salts    thereof.

The invention relates to compounds of the formula I in the form of theirracemates, enantiomer-enriched mixtures and pure enantiomers and totheir diastereomers and mixtures thereof.

The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3,R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18,R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32,R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46,R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60,R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74,R75, R76, R77, R78, R79, R80, R81, R82, R83 and R84 may be eitherstraight-chain, branched or optionally halogenated.

In a further embodiment, the alkyl, alkenyl and alkynyl radicals in thesubstituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13,R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27,R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41,R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55,R56, R57, R58, R59, R60, R61, R62. R63, R64, R65, R66, R67, R68, R69,R70, R71, R72, R73, R74, R75, R76, R77, R78, R79. R80, R81, R82, R83 andR84 may be both straight-chain, branched and/or optionally substitutedby substituents such as aryl, heteroaryl, alkoxy or halogen. This alsoapplies if the alkyl, alkenyl and alkynyl radicals are part of anothergroup, for example part of an alkoxy group (such as(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl)). Suitable halogens are fluorine,chlorine, bromine and iodine, preferably fluorine, chlorine and bromine,particularly preferably fluorine.

Examples of alkyl groups are: methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl and octyl. Included therein are both the n isomers ofthese radicals and branched isomers such as isopropyl, isobutyl,isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl etc.Unless described otherwise, the term alkyl additionally includes alkylradicals which are unsubstituted or optionally substituted by one ormore further radicals, for example 1, 2, 3 or 4 identical or differentradicals such as aryl, heteroaryl, alkoxy or halogen. It is moreoverpossible for the additional substituents to occur in any position of thealkyl radical.

Cycloalkyl means for the purposes of the present application cycloalkyland cycloalkyl-alkyl(alkyl which is substituted in turn by cycloalkyl,e.g. cyclopropylmethyl), where cycloalkyl has at least 3 carbon atoms.Examples of cycloalkyl radicals are: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl andcyclodecyl. Optional possibilities are also polycyclic ring systems suchas decalinyl, norbornanyl, bornanyl or adamantanyl. The cycloalkylradicals may be unsubstituted or optionally substituted by one or morefurther radicals as listed above by way of example for the alkylradicals.

Examples of alkenyl and alkynyl groups are: vinyl, 1-propenyl,2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl,ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl or3-butynyl.

Cycloalkenyl means for the purposes of the present applicationcycloalkenyl radicals and cycloalkenyl-alkyl radicals (alkyl which issubstituted by cycloalkenyl), which comprise at least three carbonatoms. Examples of cycloalkenyl are: cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl. The alkenyl radicals and cycloalkenylradicals may have one to three conjugated or unconjugated double bonds(thus also alk-dienyl and alk-trienyl radicals), preferably one doublebond in a straight or branched chain. The same applies to the triplebonds in alkynyl radicals. The alkenyl and alkynyl radicals may beunsubstituted or optionally substituted by one or more further radicalsas listed above by way of example for the alkyl radicals.

Aryl refers in the present invention to radicals derived from monocyclicor bicyclic aromatic compounds comprising no ring heteroatoms. Wherearyl refers to systems which are not monocyclic, the saturated form(perhydroform) or the partially unsaturated form (for example thedihydroform or tetrahydroform) is also possible, where the respectiveforms are known and stable, for the second ring. The term aryl alsoincludes in the present invention for example bicyclic radicals in whichboth rings are aromatic and bicyclic radicals in which only one ring isaromatic. Examples of aryl are: phenyl, naphthyl, indanyl,1,2-dihydronaphthenyl, 1,4-dihydronaphthenyl, indenyl or1,2,3,4-tetrahydronaphthyl. Aryl is particularly preferably phenyl ornaphthyl. The term “aryl” thus means in particular a phenyl or naphthylgroup.

Heteroaryl radicals mean radicals derived from monocyclic or bicyclicaromatic compounds comprising ring heteroatoms, preferably N, O or S.Otherwise, the statements made about aryl radicals apply to heteroarylradicals.

The aryl and heteroaryl radicals may be unsubstituted or substituted byone or more further radicals. Suitable further radicals are listed byway of example above for the alkyl radicals.

The compounds of the formula I may comprise one or more centers ofasymmetry. The compounds of the formula I may therefore be in the formof their racemates, enantiomer-enriched mixtures, pure enantiomers,diastereomers and diastereomer mixtures. The present invention includesall these isomeric forms of the compounds of the formula I. Theseisomeric forms can be obtained by known methods even if not expresslydescribed in some cases.

Mono-, bi- or spirocyclic rings may be saturated, partially saturated orunsaturated and also bridged.

C═C means a group of the formula R′C═CR″ in which R′ and R″ areindependently of one another H, (C₁-C₈)-alkyl, preferably H.

In the case where R1 and R2 together with the nitrogen atom to whichthey are bonded form a ring, this ring may be substituted by one or moreof the substituents mentioned.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because their solubility in water is higher than theinitial or basic compounds. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the compounds according to the invention are salts ofinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric,metaphosphoric, nitric and sulfuric acids, and organic acids such as,for example, acetic acid, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic,succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. Thechloride salt is particularly preferably used for medical purposes.Suitable pharmaceutically acceptable basic salts are ammonium salts,alkali metal salts (such as sodium and potassium salts) and alkalineearth metal salts (such as magnesium and calcium salts) and salts oftrometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine,lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion likewise fall withinthe scope of the invention as useful intermediates for preparing orpurifying pharmaceutically acceptable salts and/or for use innontherapeutic, for example in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound according to theinvention of the formula I, for example an ester, which is able onadministration to a mammal such as, for example, a human to form(directly or indirectly) a compound of the formula I or an activemetabolite thereof.

The physiologically functional derivatives also include prodrugs of thecompounds according to the invention, as described, for example, in H.Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can bemetabolized in vivo to a compound according to the invention. Theseprodrugs may themselves be active or not.

The compounds according to the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds according tothe invention lie within the scope of the invention and are a furtheraspect of the invention.

All references hereinafter to “compound(s) of formula (I)” refer tocompound(s) of the formula (I) as described above, and the salts,solvates and physiologically functional derivatives thereof as describedherein.

If radicals or substituents can occur more than once in the compounds ofthe formula I, they may all independently of one another have the statedmeanings and be identical or different.

In a preferred embodiment, the meanings in the compounds of the formulaI are

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,    —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,    CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(s)O(R21); or R1 and    R2 form together with the nitrogen atom to which they are bonded a 4    to 10-membered mono-, bi- or spirocyclic ring which, apart from the    nitrogen atom, may include 0 to 4 additional heteroatoms selected    from the group of oxygen, nitrogen and sulfur, where the    heterocyclic ring system may additionally be substituted by F, Cl,    Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,    (C₀-C₈)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy,    COO(R25), N(R26)CO(C₁-C₆)-alkyl or N(R27)(R28);-   R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33),    3-12 membered mono-, bi- or spirocyclic ring which may comprise one    or more heteroatoms from the group of N, O and S, and the 3-12    membered ring may comprise further substituents such as F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl,    O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),    CO(C₁-C₆)-alkyl and COO(R36); and-   R6, R7, R8, R9 independently of one another H, (C₁-C₈)-alkyl;    where the further radicals and groups in the compounds of the    formula I have the meanings mentioned hereinbefore and preferred    meanings mentioned hereinafter.

In a further preferred embodiment, the present invention relates tocompounds of the formula I

the meanings are:

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,    —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12, CO(C(R15)(R16))_(q)N(R17)(R18),    CO(C(R19)(R20))_(s)O(R21); or R1 and R2 form together with the    nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi-    or spirocyclic ring which, apart from the nitrogen atom, may include    0 to 2 additional heteroatoms selected from the group of oxygen,    nitrogen and sulfur, where the heterocyclic ring system may    additionally be substituted by F, Cl, CF₃, (C₁-C₆)-alkyl,    O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R22),    CON(R23)(R24), hydroxy, COO(R25), N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28)    or SO₂CH₃;    -   preferably independently of one another H, (C₁-C₈)-alkyl,        —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,        CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(s)O(R21); or R1        and R2 form together with the nitrogen atom to which they are        bonded a 4 to 10-membered mono- or bicyclic ring which, apart        from the nitrogen atom, may include 0 to 2 additional        heteroatoms selected from the group of oxygen, nitrogen and        sulfur, where the heterocyclic ring system may additionally be        substituted by F, Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo,        CO(R22), hydroxy, N(R27)(R28) or SO₂CH₃;    -   particularly preferably independently of one another H,        (C₁-C₈)-alkyl, —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,        CO(C(R15)(R16))_(q)N(R17)(R18), or R1 and R2 form together with        the nitrogen atom to which they are bonded a 4 to 10-membered        mono- or bicyclic ring which, apart from the nitrogen atom, may        include 0 to 2 additional heteroatoms selected from the group of        oxygen and nitrogen, where the heterocyclic ring system may        additionally be substituted by F, (C₁-C₆)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, oxo, CO(R22), hydroxy,        N(R27)(R28);-   o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly    preferably 0, 1, 2, 3;-   q 1, 2, 3; preferably 1 or 2;-   s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0,    1, 2;-   R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28    independently of one another H, (C₁-C₆)-alkyl; or-   R17 and R18, R23 and R24, R27 and R28 independently of one another    optionally together with the nitrogen atom to which they are bonded    a 5-6 membered ring which, apart from the nitrogen atom, may also    include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur; the ring is preferably    pyrrolidine, piperidine, N-methylpiperazine, morpholine;-   R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), 3-12 membered    mono-, bi- or spirocyclic ring which may comprise one or more    heteroatoms from the group of N, O and S, and the 3-12 membered ring    may comprise further substituents such as F, Cl, Br, OH, CF₃, CN,    oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl,    O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),    CO(C₁-C₆)-alkyl, COO(R36), S(O)_(u)(R37);    -   preferably OH, O—(C₁-C₆)-alkyl, CN, 3-10 membered mono- or        bicyclic ring which may comprise 1-3 heteroatoms from the group        of N, O and S, and the 3-10 membered ring may comprise further        substituents such as F, Cl, Br, OH, CF₃, CN, oxo,        O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl,        (C₀-C₂)-alkylene-aryl, N(R34)(R35), CO(C₁-C₆)-alkyl;    -   particularly preferably OH, O—(C₁-C₆)-alkyl, 3-10 membered mono-        or bicyclic ring which may comprise 1-2 heteroatoms from the        group of N, O and S, and the 3-10 membered ring may comprise        further substituents such as F, OH, oxo, (C₁-C₆)-alkyl,        CO(C₁-C₆)-alkyl;-   u 0, 1, 2; preferably 0 or 2; particularly preferably 2;-   R34, R35 independently of one another H, (C₁-C₈)-alkyl; or-   R34 and R35 optionally together with the nitrogen atom to which they    are bonded a 5-6 membered ring which, apart from the nitrogen atom,    may also include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur, and optionally be substituted by    1-2 oxo groups;-   R36, R37 H, (C₁-C₈)-alkyl;-   R13, R14 independently of one another H, (C₁-C₈)-alkyl,    hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;-   R29, R30, R31 independently of one another H, (C₁-C₈)-alkyl;-   R3 H, (C₁-C₆)-alkyl; preferably H;-   R4, R5 independently of one another H, (C₁-C₆)-alkyl, OH,    O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl; preferably    independently of one another H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl,    O—CO(C₁-C₆)-alkyl;    -   particularly preferably independently of one another H, OH,        O—(C₁-C₆)-alkyl, very particularly preferably H;-   R6, R7, R8, R9 H; or-   R6 and R7, R8 and R9 independently of one another optionally oxo;-   R6, R7, R8, R9 are preferably H;-   n 1-   m 1 or 2; preferably 1;-   A, B, D, G independently of one another N, C(R38); or    -   the groups A and B or D and G are in each case C(R38) and        together form an ortho-phenylene unit so that the overall result        is a 1,4-bisubstituted naphthalene system;    -   preferably A, B, G and D are independently of one another N,        C(R38); particularly preferably D and G are C(R38) and either A        or B is N, with the respective other group B or A being C(R38);        very particularly preferably    -   B is N, C(R38); and A, D, G C(R38);    -   especially preferably    -   A, B, D, G are C(R38);-   R38 H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, N(R39)(R40),    SO₂—CH₃, CON(R41)(R42), N(R43)CO(R44), CO(R47),    —(CR48R49)_(n)—O(R50);    -   preferably H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl,        (C₁-C₆)-alkyl, SO₂—CH₃, CON(R41)(R42), N(R43)CO(R44), CO(R47),        —(CR48R49)_(x)—O(R50);    -   particularly preferably H, F, Cl, CF₃, CN, (C₁-C₆)-alkyl,        —(CR48R49)_(x)—O(R50);-   R39, R40, R41, R42, R43 independently of one another H,    (C₁-C₈)-alkyl; or-   R39 and R40, R41 and R42 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur;-   R44, R47 independently of one another H, (C₁-C₈)-alkyl, aryl;    preferably independently of one another H, (C₁-C₈)-alkyl;-   R48, R49 H;-   R50 H, (C₁-C₆)-alkyl;-   x 1, 2; preferably 1;-   Het five-membered aromatic heterocycle, preferably

-   -   in which    -   A′ is O, S, NR73,    -   X′, Y′ and Z′ are independently of one another CR74 or N, and    -   R73, R74 are independently of one another H, (C₁-C₈)-alkyl;    -   Het is particularly preferably selected from the group        consisting of oxadiazoles, thiadiazoles, thiazoles, oxazoles,        triazoles, thiophenes, furans and pyrroles; Het is very        particularly preferably selected from oxadiazoles, thiadiazoles,        thiazoles and oxazoles;

-   X a bond, a group of the formula —(CR51R52)_(y)-in which one or more    —(CR51R52)-groups may be replaced by Y to result in a chemically    reasonable radical, C═C, C≡C; preferably a bond, CH₂—CH₂, CH₂Y,    YCH₂, (R75)YCH₂, CH₂—NCO(R75), CH₂CON(R75); C(R76)(R77),    C(R78)(R79)O, N(R75), C═C, C≡C; particularly preferably a bond,    CH₂—CH₂, C(R76)(R77), N(R75), CH₂Y, CH₂Y(R75), CH₂—NCO(R75),    CH₂CON(R75); C═C; very particularly preferably a bond, CH₂—CH₂,    C(R76)(R77), C═C, (R75)YCH₂, CH₂—NCO(R75);

-   Y O, S, N(R53), CO; preferably O, S, N(R53);

-   R53 H, (C₁-C₈)-alkyl;

-   R75, R76, R77, R78, R79 independently of one another H,    (C₁-C₈)-alkyl;

-   E 3-8 membered bivalent carbo- or heterocyclic ring structure having    0-4 heteroatoms from the group of N, O and S, which may optionally    have substituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, CN,    OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    O—(C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,    O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R54)(R55), SO₂—CH₃,    N(R58)CO(R59), N(R60)SO₂(R61), CO(R62) and be mono- or bicyclic;    -   preferably 5-7 membered bivalent carbo- or heterocyclic ring        structure having 0-3 heteroatoms from the group of N, O and S,        which may optionally have substituents from the group of H, F,        Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,        S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R54)(R55), SO₂—CH₃,        N(R58)CO(R59), CO(R62) and be mono- or bicyclic;    -   particularly preferably 5-7 membered bivalent carbo- or        heterocyclic ring structure having 0-2 heteroatoms from the        group of N, O and S, which may optionally have substituents from        the group of H, F, Cl, Br, OH, CF₃, NO₂, OCF₃, O—(C₁-C₆)-alkyl,        (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R54)(R55), SO₂—CH₃, CO(R62),        and which is very particularly preferably monocyclic;    -   e.g. E is benzene, pyridine, pyrimidine, piperidine,        pyrrolidine, cyclopentane, cyclohexane, piperazine,        homopiperazine, thiazole, thiophene, furan, pyrrole, pyrazole,        1,2,3,6-tetrahydropyridine, 4,5-dihydroisoxazole, oxazole;

-   R54, R55, R58, R60 independently of one another H, (C₁-C₈)-alkyl;    -   R59, R61, R62 independently of one another H, (C₁-C₈)-alkyl,        aryl; preferably independently of one another H, (C₁-C₈)-alkyl;

-   K O, a bond, CH₂O, OCH₂, S, SO, SO₂, N(R80), N(R81)CO, CON(R82),    (C(R83)(R84))_(v), CO, C═C, C≡C, SCH₂, SO₂CH₂; preferably 0, a bond,    CH₂O, OCH₂, N(R80), N(R81)CO, CON(R82), (C(R83)(R84))_(v), CO, C≡C,    SCH₂; particularly preferably 0, a bond, CH₂O, OCH₂, CON(R82),    (C(R83)(R84))_(v), CO, C≡C;

-   v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1, 2;

-   R80, R81, R82, R83, R84 independently of one another H,    (C₁-C₈)-alkyl;

-   R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring    which may include 0 to 4 heteroatoms selected from the group of    oxygen, nitrogen and sulfur, where the ring system may additionally    be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,    O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R66),    CON(R67)(R68), hydroxy, COO(R69), N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72)    or SO₂CH₃;    -   preferably (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to        10-membered mono-, bi- or spirocyclic ring which may include 0        to 3 heteroatoms selected from the group of oxygen, nitrogen and        sulfur, where the ring system may additionally be substituted by        F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,        (C₀-C₂)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68), hydroxy,        N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72) or SO₂CH₃;    -   particularly preferably (C₁-C₈)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono- or        bicyclic ring which may include 0 to 2 heteroatoms selected from        the group of oxygen, nitrogen and sulfur, where the ring system        may additionally be substituted by F, Cl, Br, CF₃, CN,        (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R66), CON(R67)(R68),        N(R70)CO(C₁-C₆)-alkyl, or SO₂CH₃;

-   R66, R67, R68, R69, R70, R71, R72 independently of one another H,    (C₁-C₈)-alkyl; or

-   R67 and R68, R71 and R72 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur; or    the N-oxides thereof and the physiologically tolerated salts    thereof.

In a preferred embodiment of the invention, the radicals R1, R2, R11,R38 and groups X, E, K have the following meanings:

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,    —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or R1 and R2 form    together with the nitrogen atom to which they are bonded a 4 to    10-membered mono-, bi- or spirocyclic ring which, apart from the    nitrogen atom, may include 0 to 2 additional heteroatoms selected    from the group of oxygen, nitrogen and sulfur, where the    heterocyclic ring system may additionally be substituted by    (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    hydroxy-(C₁-C₄)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R22),    CON(R23)(R24), hydroxy, N(R27)(R28) or SO₂CH₃;    -   preferably independently of one another H, (C₁-C₈)-alkyl,        —(CR13R14)_(o)—, R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or R1 and R2        form together with the nitrogen atom to which they are bonded a        4 to 10-membered mono-, bi- or spirocyclic ring which, apart        from the nitrogen atom, may include 0 to 2 additional        heteroatoms selected from the group of oxygen, nitrogen and        sulfur, where the heterocyclic ring system may additionally be        substituted by (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,        (C₀-C₂)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy or        N(R27)(R28);    -   very particularly preferably independently of one another H,        (C₁-C₈)-alkyl, or R1 and R2 form together with the nitrogen atom        to which they are bonded a 5 to 6-membered monocyclic ring        which, apart from the nitrogen atom, may include 0 to 1        additional heteroatoms selected from the group of oxygen,        nitrogen and sulfur, where the heterocyclic ring system may        additionally be substituted by (C₁-C₆)-alkyl;    -   especially preferably independently of one another H,        (C₁-C₈)-alkyl;-   o 0, 1, 2, 3, 4;-   R22, R23, R24, R27, R28 independently of one another H,    (C₁-C₆)-alkyl; or-   R23 and R24, R27 and R28 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur;-   R12 OH, O—(C₁-C₆)-alkyl, CN, 3-12 membered mono-, bi- or spirocyclic    ring which may comprise 1 to 3 heteroatoms from the group of N, O    and S, and the 3-12 membered ring may comprise further substituents    such as F, OH, CF₃, CN, oxo, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl,    N(R34)(R35), COO(R36), CO(C₁-C₆)-alkyl;-   R34, R35 independently of one another H, (C₁-C₄)-alkyl;-   R36 H, (C₁-C₆)-alkyl;-   R13, R14 independently of one another H, (C₁-C₈)-alkyl,    hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;-   R38 H, F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl;-   X a bond, CH₂CH₂, C(R76)(R77), N(R75), C═C, (R75)YCH₂, CH₂—NCO(R75),    CH₂CON(R75);-   Y O, S, N(R53), CO-   R75, R76, R77 independently of one another H, (C₁-C₈)-alkyl;-   R53 H, (C₁-C₈)-alkyl;-   E 5-7 membered bivalent carbo- or heterocyclic ring structure having    0-3 heteroatoms from the group of N, O and S, which may optionally    have substituents from the group of H, F, Cl, Br, CF₃, OH, CN, OCF₃,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SO₂—CH₃, CO(R65);-   R65 H, (C₁-C₈)-alkyl;-   K O, a bond, CH₂O, CH₂, OCH₂, S, SO₂, N(R80), N(R81)CO, CON(R82),    (C(R83)(R84))_(v), CO, C≡C, SCH₂, SO₂CH₂; preferably O, a bond,    CH₂O, CH₂, OCH₂, N(R80), C≡C;-   v 1, 2, 3;-   R80, R81, R82, R83, R84 independently of one another H,    (C₁-C₈)-alkyl;-   R11 (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered    mono-, bi- or spirocyclic ring which may include 0 to 4 heteroatoms    selected from the group of oxygen, nitrogen and sulfur, where the    ring system may additionally be substituted by F, Cl, Br, CF₃, CN,    (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo, CO(R66), hydroxy,    N(R70)CO(C₁-C₆)-alkyl, or SO₂CH₃;-   R66, R70 independently of one another H, (C₁-C₈)-alkyl;    the N-oxides thereof and the physiologically tolerated salts    thereof.

Particularly preferred compounds of the formula I are those in which

-   A, B, D, G are independently of one another N or C(R38), and the    total number of nitrogen atoms in this ring is 0-2, preferably 0 or    1, and in the case where the total number of nitrogen atoms is 1,    particularly preferably A or B are N, and very particularly    preferably B is N.

Very particularly preferred compounds of the formula I are those inwhich

-   n is 1 and-   m is 1 or 2.

Especially preferred compounds of the formula I are those in which

-   A, B, D, G are independently of one another N or C(R38), and the    total number of nitrogen atoms in this ring is 0-2, preferably 0 or    1, and in the case where the total number of nitrogen atoms is 1,    particularly preferably A or B are N, and very particularly    preferably B is N.-   n is 1 and-   m is 1 or 2.

The radical R38 has the aforementioned meanings.

Especially preferred compounds of the formula I are those in which

-   Het is selected from the group consisting of oxadiazoles,    thiadiazoles, thiazoles, oxazoles, triazoles, thiophenes, furans and    pyrroles; Het is very particularly preferably selected from    oxadiazoles, thiadiazoles, thiazoles and oxazoles.

The further radicals may have the aforementioned meanings in theaforementioned preferred embodiments.

In a very particularly preferred embodiment, the present applicationrelates to compounds of the formula IA

in which the meanings are

-   -   in which    -   A′ is O, S,    -   X′ and Y′ are independently of one another CR74 or N, and    -   R74 are independently of one another H, (C₁-C₈)-alkyl;

-   A, B are CH or CF, where in the case of CF only one of the two    groups A or B is CF and the other group is CH;

-   R1, R2 independently of one another H, (C₁-C₈)-alkyl,    —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,    CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(s)O(R21); or R1 and    R2 form together with the nitrogen atom to which they are bonded a 4    to 10-membered mono-, bi- or spirocyclic ring which, apart from the    nitrogen atom, may include 0 to 4 additional heteroatoms selected    from the group of oxygen, nitrogen and sulfur, where the    heterocyclic ring system may additionally be substituted by F, Cl,    Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,    (C₀-C₈)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy,    COO(R25), N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28) or SO₂CH₃;    -   particularly preferably independently of one another H,        (C₁-C₈)-alkyl, —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12; or R1 and R2 form together        with the nitrogen atom to which they are bonded a 4 to        10-membered mono-, bi- or spirocyclic ring which, apart from the        nitrogen atom, may include 0 to 4 additional heteroatoms        selected from the group of oxygen, nitrogen and sulfur, where        the heterocyclic ring system may additionally be substituted by        F, Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,        (C₀-C₈)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxyl,        N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28);    -   very particularly preferably independently of one another H,        (C₁-C₈)-alkyl, —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,        —CO—(CH₂)_(o)—R12; or R1 and R2 form together with the nitrogen        atom to which they are bonded a 4 to 7-membered monocyclic ring        which, apart from the nitrogen atom, may include 0 to 2        additional heteroatoms selected from the group of oxygen,        nitrogen and sulfur, where the heterocyclic ring system may        additionally be substituted by F, Cl, CF₃, (C₁-C₆)-alkyl,        O—(C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, CO(R22), CON(R23)(R24),        hydroxy, N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28);    -   especially preferably independently of one another H,        (C₁-C₈)-alkyl, or R1 and R2 form together with the nitrogen atom        to which they are bonded a 5 to 6-membered monocyclic ring        which, apart from the nitrogen atom, may include 0 to 1        additional heteroatoms selected from the group of oxygen,        nitrogen and sulfur, where the heterocyclic ring system may        additionally be substituted by (C₁-C₆)-alkyl;    -   further very particularly preferably independently of one        another H, (C₁-C₈)-alkyl;

-   o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4;

-   q, s independently of one another 0, 1, 2, 3, 4;

-   R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28    independently of one another H, (C₁-C₆)-alkyl;

-   R17 and R18, R23 and R24, R27 and R28 independently of one another    optionally together with the nitrogen atom to which they are bonded    a 5-6 membered ring which, apart from the nitrogen atom, may also    include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur;

-   R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33),    3-12 membered mono-, bi- or spirocyclic ring which may comprise one    or more heteroatoms from the group of N, O and S, and the 3-12    membered ring may comprise further substituents such as F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl,    O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),    CO(C₁-C₆)-alkyl, COO(R36) and S(O)_(u)(R37); particularly preferably    OH, O—(C₁-C₆)-alkyl, CN, CON(R30)(R31), N(R32)(R33), 3-7 membered    monocyclic ring which may comprise one or more heteroatoms from the    group of N, O and S, and the 3-7 membered ring may comprise further    substituents such as F, Cl, OH, CF₃, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,    (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl,    O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35) and    CO(C₁-C₆)-alkyl;

-   u 0, 1, 2;

-   R34, R35 independently of one another H, (C₁-C₈)-alkyl;

-   R34 and R35 optionally together with the nitrogen atom to which they    are bonded a 5-6 membered ring which, apart from the nitrogen atom,    may also include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur and optionally be substituted by    1-2 oxo groups;

-   R36, R37 H, (C₁-C₈)-alkyl;

-   R13, R14 independently of one another H, (C₁-C₈)-alkyl,    hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;

-   R29, R30, R31 independently of one another H, (C₁-C₈)-alkyl,    (C₂-C₆)-alkenyl, (C₀-C₈)-alkylene-aryl;

-   R32, R33 independently of one another H, (C₁-C₆)-alkyl or

-   R32 and R33 optionally together with the nitrogen atom to which they    are bonded a 5-6 membered ring, which, apart from the nitrogen atom,    may also include 0-1 further heteroatoms from the group of NH,    N—(C₁-C₆)-alkyl, oxygen and sulfur and optionally be substituted by    1-2 oxo groups;

-   X a bond, a group of the formula —(CR51R52)_(y)-in which one or more    —(CR51R52)-groups may be replaced by Y to result in a chemically    reasonable radical, C═C, C≡C; preferably a bond, CH₂—CH₂, CH₂Y,    YCH₂, (R75)YCH₂, CH₂—NCO(R75), CH₂CON(R75); C(R76)(R77),    C(R78)(R79)O, N(R75), C═C, C≡C; particularly preferably a bond,    CH₂—CH₂, C(R76)(R77), N(R75), CH₂Y, CH₂Y(R75), CH₂—NCO(R75),    CH₂CON(R75); C═C; very particularly preferably a bond, CH₂—CH₂,    C(R76)(R77), C═C; (R75)YCH₂, CH₂—NCO(R75);

-   Y O, S, N(R53), CO, SO, SO₂; particularly preferably O, S, N(R53),    CO; very particularly preferably O, N(R53);

-   R51, R52 independently of one another H, (C₁-C₄)-alkyl, where R51    and R52 in the y groups in each case can have the same or different    meanings;

-   y 1, 2, 3, 4, 5, 6;

-   R53 H, (C₁-C₈)-alkyl;

-   E 3-14 membered bivalent carbo- or heterocyclic ring structure    having 0-4 heteroatoms from the group of N, O and S, which may    optionally have substituents from the group of H, F, Cl, Br, I, OH,    CF₃, NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl,    S-aryl, N(R54)(R55), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl,    CON(R56)(R57), N(R58)CO(R59), N(R60)SO₂(R61), CO(R62) and be mono-    or bicyclic;    -   preferably 5-7 membered bivalent carbo- or heterocyclic ring        structure having 0-3 heteroatoms from the group of N, O and S,        which may optionally have substituents from the group of H, F,        Cl, OH, CN, CF₃, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,        (C₀-C₈)-alkylene-aryl, O—(C₃-C₈)-cycloalkyl, N(R54)(R55),        SO₂—CH₃, CON(R56)(R57), N(R58)CO(R59), N(R60)SO₂(R61), CO(R62)        and be mono- or bicyclic; particularly preferably 5-7 membered        bivalent carbo- or heterocyclic ring structure having 0-3        heteroatoms from the group of N, O and S, which may optionally        have substituents from the group of H, F, Cl, CF₃, OCF₃,        O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl,        O—(C₃-C₆)-cycloalkyl, N(R54)(R55), CON(R56)(R57), N(R58)CO(R59),        CO(R62) and be mono- or bicyclic;

-   R54, R55, R56, R57, R58, R60 independently of one another H,    (C₁-C₈)-alkyl;

-   R54 and R55, R56 and R57 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur;

-   R59, R61, R62 independently of one another H, (C₁-C₈)-alkyl, aryl;

-   K a bond, a group of the formula —(CR63R64)_(z)—, in which one or    more —(CR63R64)-groups may be replaced by Z to result in a    chemically reasonable radical, C≡C, C═C;    -   preferably O, a bond, CH₂O, CH₂, OCH₂, S, SO₂, N(R80), N(R81)CO,        CON(R82), (C(R83)(R84))_(v), CO, C≡C, SCH₂, SO₂CH₂;

-   Z O, S, N(R65), CO, SO, SO₂;

-   R63, R64 independently of one another H, (C₁-C₈)-alkyl, hydroxy,    (C₁-C₆)-alkoxy, where R63 and R64 in the z groups may in each case    have the same or different meanings;

-   z 1, 2, 3, 4, 5, 6, preferably 2, 3, 4, 5, 6;

-   R65 H, (C₁-C₈)-alkyl;

-   R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl,    (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring    which may include 0 to 4 heteroatoms selected from the group of    oxygen, nitrogen and sulfur, where the ring system may additionally    be substituted by F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl,    O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    (C₀-C₈)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68), hydroxy,    hydroxy-(C₁-C₄)-alkyl, COO(R69), N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72)    or SO₂CH₃;    -   preferably H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 5        to 6-membered monocyclic ring which may include 0 to 3        heteroatoms selected from the group of oxygen, nitrogen and        sulfur, where the ring system may additionally be substituted by        F, Cl, Br, CF₃, NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, CO(R66), CON(R67)(R68), hydroxy,        N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72) or SO₂CH₃;    -   particularly preferably H, (C₁-C₈)-alkyl,        (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 5 to 6-membered monocyclic ring        which may include 0 to 2 heteroatoms selected from the group of        oxygen, nitrogen and sulfur, where the ring system may        additionally be substituted by F, Cl, Br, CF₃, NO₂, CN,        (C₁-C₆)-alkyl or O—(C₁-C₈)-alkyl;

-   R66, R67, R68, R69, R70, R71, R72 independently of one another H,    (C₁-C₈)-alkyl; or

-   R67 and R68, R71 and R72 independently of one another optionally    together with the nitrogen atom to which they are bonded a 5-6    membered ring which, apart from the nitrogen atom, may also include    0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,    oxygen and sulfur; or    the N-oxides thereof and the physiologically tolerated salts    thereof.

The compounds of the invention of the formula I and their precursors canbe prepared by processes known to the skilled worker.

The preparation of compounds of the invention of the formula I isdescribed below for the example of the preparation of[1,3,4]-oxadiazoles (Ia), [1,3,4]-thiadiazoles (Ib) and[1,2,4]-oxadiazoles (Ic):

in which

-   R is H, (C₁-C₈)-alkyl, and-   R1 and R2 have the aforementioned meanings;

or Burgess' reagent

in which R1, R2, R11 and X, E and K have the aforementioned meanings.

in which R1, R2, R11 and X, E and K have the aforementioned meanings.Use

This invention further relates to the use of compounds of the formula Iand their pharmaceutical compositions as MCH receptor ligands. The MCHreceptor ligands of the invention are particularly suitable asmodulators of the activity of the MCH1R.

The role of MCH in regulating the energy balance has now been welldocumented (Qu, D. et al.; Nature 1996, 380, 243-7; Shimada, M. et al.Nature 1998, 396, 670-4; Chen, Y. et al. Endocrinology 2002, 143,2469-77; Endocrinology 2003, 144, 4831-40; Review: G. Hervieu, ExpertOpin. Ther. Targets 2003, 7, 495-511).

There are also indications that MCH antagonists can have a beneficialinfluence on centrally related disorders such as, for example,depression (Borowsky, B. et al.; Nature Medicine 2002, 8, 825-30;Review: G. Hervieu, Expert Opin. Ther. Targets 2003, 7, 495-511).

Compounds of this type are particularly suitable for the treatmentand/or prevention of

-   1. Obesity-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.-   Particular aspects in this connection are    -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,    -   protection of the pancreatic β cells    -   prevention of macro- and microvascular disorders-   3. Dyslipidemias and their sequelae such as, for example,    atherosclerosis, coronary heart disease, cerebrovascular disorders    etc., especially those (but not restricted thereto) which are    characterized by one or more of the following factors:    -   high plasma triglyceride concentrations, high postprandial        plasma triglyceride concentrations,    -   low HDL cholesterol concentration-   4. Various other conditions which may be associated with the    metabolic syndrome, such as:    -   thromboses, hypercoagulable and prothrombotic stages (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   5. Psychiatric indications such as    -   depression    -   anxiety states    -   disturbances of the circadian rhythm    -   affection disorders    -   schizophrenia    -   addictive disorders        Formulations

The amount of a compound of formula (I) which is necessary to achievethe desired biological effect depends on a number of factors, forexample the specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. In general,the daily dose is in the range from 0.001 mg to 100 mg, preferably from0.3 mg to 100 mg (typically from 0.01 mg to 50 mg, preferably from 3 mgto 50 mg) per day per kilogram of body weight, for example 0.1-10mg/kg/day, preferably 3-10 mg/kg/day. An intravenous dose may be, forexample, in the range from 0.001 mg to 1.0 mg/kg, preferably from 0.3 mgto 1.0 mg/kg, which can most suitably be administered as infusion offrom 10 ng to 100 ng per kilogram and per minute. Suitable infusionsolutions for these purposes may contain, for example, from 0.1 ng to 10mg, typically from 1 ng to 10 mg, per milliliter. Single doses maycontain, for example, from 1 mg to 10 g of the active ingredient. Singledoses may contain, for example, from 1 mg to 10 g of the activeingredient. It is thus possible for ampoules for injections to contain,for example, from 1 mg to 100 mg, and for single-dose formulations whichcan be administered orally, such as, for example, tablets or capsules,to contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600mg, or in a further embodiment from 1.0 to 1000 mg, typically from 10 to600 mg. In the case of pharmaceutically acceptable salts, theaforementioned weight data are based on the weight of the salt of theunderlying free compound. For the prophylaxis or therapy of theabovementioned conditions, the compounds of formula (I) can be used asthe compound itself, but they are preferably in the form of apharmaceutical composition with an acceptable carrier. The carrier must,of course, be acceptable in the sense that it is compatible with theother ingredients of the composition and is not hazardous for thepatient's health. The carrier may be a solid or a liquid or both and ispreferably formulated with the compound as a single dose, for example asa tablet which may contain from 0.05% to 95% by weight of the activeingredient. Further pharmaceutically active substances may likewise bepresent, including other compounds of formula (I). The pharmaceuticalcompositions according to the invention can be produced by one of theknown pharmaceutical methods which essentially consist of mixing theingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions according to the invention are thosesuitable for oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration although the most suitable mode ofadministration in each individual case depends on the nature andseverity of the condition to be treated and on the nature of thecompound of formula (I) used in each case. Coated formulations andcoated slow-release formulations also lie within the scope of theinvention. Formulations resistant to acid and gastric fluid arepreferred. Suitable coatings resistant to gastric fluid comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units such as, for example, capsules, cachets,suckable tablets or tablets, each of which contain a defined amount ofthe compound of formula (I); as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. In general, thecompositions are produced by uniform and homogeneous mixing of theactive ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form, such as, for example, a powder or granules, whereappropriate mixed with a binder, lubricant, inert diluent and/or a(plurality of) surface-active/dispersing agent(s) in a suitable machine.Molded tablets can be produced by molding the compound which is inpowder form and is moistened with an inert liquid diluent in a suitablemachine.

Pharmaceutical compositions suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula (I) with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula (I), which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions according to the invention generally contain from 0.1 to 5%by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula (I) with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application to the skinare preferably in the form of ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anoptionally buffered aqueous solution, dissolved and/or dispersed in anadhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. As aspecial possibility, the active ingredient can be released as described,for example, in Pharmaceutical Research, 2(6): 318 (1986) byelectrotransport or iontophoresis.

The compounds of the formula I are distinguished by beneficial effectson lipid metabolism, and they are particularly suitable for weightreduction and for maintaining a reduced weight after weight reductionhas taken place in mammals and as anorectic agents. The compounds aredistinguished by their low toxicity and their few side effects.

The compounds can be employed alone or in combination with otherweight-reducing or anorectic active ingredients. Further anorecticactive ingredients of this type are mentioned, for example, in the RoteListe, chapter 01 under weight-reducing agents/appetite suppressants,and may also include active ingredients which increase the energyturnover of the organism and thus lead to weight reduction or else thosewhich influence the general metabolism of the organism in such a waythat an increased calorie intake does not lead to an enlargement of thefat depots and a normal calorie intake leads to a reduction of the fatdepots of the organism. The compounds are suitable for the prophylaxisand, in particular, for the treatment of excessive weight or obesity.The compounds are further suitable for the prophylaxis and, inparticular, for the treatment of type II diabetes, of arteriosclerosisand for normalizing lipid metabolism and for the treatment of high bloodpressure.

Combinations with Other Medicaments

In a further aspect of the invention, the compounds of the formula I canbe administered in combination with one or more other pharmacologicallyactive substances which have, for example, favorable effects onmetabolic disturbances or disorders frequently associated therewith.Examples of such medicaments are

-   1. medicaments which lower blood glucose, antidiabetics,-   2. active ingredients for the treatment of dyslipidemias,-   3. antiatherosclerotic medicaments,-   4. antiobesity agents,-   5. antiinflammatory active ingredients-   6. active ingredients for the treatment of malignant tumors-   7. antithrombotic active ingredients-   8. active ingredients for the treatment of high blood pressure-   9. active ingredients for the treatment of heart failure and-   10. active ingredients for the treatment and/or prevention of    complications caused by diabetes or associated with diabetes.

They can be combined with the compounds of the invention of the formulaI in particular for a synergistic improvement in the effect.Administration of the active ingredient combination can take placeeither by separate administration of the active ingredients to thepatient or in the form of combination products in which a plurality ofactive ingredients are present in one pharmaceutical preparation.

Further pharmacologically active substances suitable in particular are:

Antidiabetics

All antidiabetics mentioned in the Rote Liste 2001, chapter 12. They maybe combined with the compounds of the formula I of the invention inparticular for a synergistic improvement of the effect. Administrationof the active ingredient combination may take place either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation. Most of the activeingredients listed below are disclosed in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001.

Suitable antidiabetics include all insulins and insulin derivatives suchas, for example, Lantus® or HMR 1964 or Apidra®, and other fast-actinginsulins (see, e.g., U.S. Pat. No. 6,221,633), amylin, GLP-1 and GLP-2derivatives such as described in WO 01/04146 or else such as, forexample, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orallyeffective hypoglycemic active ingredients.

The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanidines, meglitinides,oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,glucagon receptor antagonists, GLP-1 agonists, DPP-IV inhibitors,potassium channel openers such as, for example, those disclosed in WO97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers,activators of insulin receptor kinase, inhibitors of GSK3-beta,inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, for example inhibitors ofglycogen phosphorylase, modulators of glucose uptake and glucoseexcretion, compounds which alter lipid metabolism and lead to a changein the lipid composition of the blood, such as antihyperlipidemic activeingredients and antilipidemic active ingredients, e.g. HMGCoA reductaseinhibitors, inhibitors of cholesterol transport/of cholesterol uptake,inhibitors of bile acid reabsorption or inhibitors of microsomaltriglyceride transfer protein (MTP), compounds which reduce food intakeand/or food absorption, PPAR and RXR agonists and active ingredientswhich act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the present compounds areadministered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with substances which influence hepaticglucose production such as, for example, glycogen phosphorylaseinhibitors (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922,WO 03/104188).

In one embodiment, the compounds of the formula I are administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.

In one embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a biguanide such as, for example, metformin.

In a further embodiment, the compounds of the formula I are administeredin combination with a meglitinide such as, for example, repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered incombination with a DPPIV inhibitor as described, for example, inWO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO 02/38541,WO03/040174, in particular P 93/01(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPARgamma agonist such as, forexample, rosiglitazone, pioglitazone.

In one embodiment, the compounds of the formula I are administered incombination with compounds with an inhibitory effect on SGLT-1 and/or 2,as disclosed directly or indirectly for example in PCT/EP03/06841,PCT/EP03/13454 and PCT/EP03/13455.

In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid Modulators

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor such aslovastatin, fluvastatin, pravastatin, simvastatin, ivastatin,itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897, U.S. Pat.No. 6,277,831, EP 0 683 773, EP 0 683 774).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol absorption inhibitor asdescribed for example in WO 0250027, or ezetimibe, tiqueside,pamaqueside.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see, forexample, U.S. Pat. No. 6,342,512).

In one embodiment, the compounds of the formula I are administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6); Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hoechst, 65926 Frankfurt/Main). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPARalpha agonist.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with nicotinic acid or niacin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, e.g. CP-529, 414(torcetrapib).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor such as, for example,implitapide.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist.

Antiobesity Agents

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor such as, forexample, orlistat.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In another embodiment, the further active ingredient is rimonabant.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amide;hydrochloride (CGP 71683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride(SB-334867-A)), CB1 antagonists/inverse agonists, H3 antagonists/inverseagonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol;hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptakeinhibitors (e.g. dexfenfluramines), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),BR53 agonists, galanin antagonists, ghrelin antagonists, MCHantagonists, mGluR5 antagonists, opioid antagonists, growth hormone(e.g. human growth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (WO 01/85695)), CNTF, CNTF derivatives (e.g.Axokine), TRH agonists (see, for example, EP 0 462 884), uncouplingprotein 2 or 3 modulators, leptin agonists (see, for example, Lee,Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso,Patricia. Leptin agonists as a potential approach to the treatment ofobesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists (e.g.bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569),PPAR modulators (e.g. WO 00/78312), RXR modulators or TR-β agonists.

In one embodiment of the invention, the further active ingredient isleptin.

In one embodiment, the further active ingredient is dexamphetamine,amphetamine, mazindole or phentermine.

In one embodiment, the compounds of the formula I are administered incombination with medicaments having effects on the coronary circulationand the vascular system, such as, for example, ACE inhibitors (e.g.ramipril), medicaments which act on the angiotensin-renin system,calcium antagonists, beta blockers etc.

In one embodiment, the compounds of the formula I are administered incombination with medicaments having an antiinflammatory effect.

In one embodiment, the compounds of the formula I are administered incombination with medicaments which are employed for cancer therapy andcancer prevention.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances is tobe regarded as covered by the scope of protection of the presentinvention.

In two articles which appeared simultaneously in Nature (Nature 400,261-264, 1999; Nature 400, 265-269, 1999), a highly specific receptorfor melanine concentrating hormone (MCH) was described separately by tworesearch groups. MCH assumes important functions in controlling foodintake. Compounds acting on the MCH receptor therefore have an anorecticeffect and are suitable for the treatment of obesity. Testing for ananorectic effect of the compounds of the invention of the formula I wastherefore carried out as follows.

Functional Measurements to Find IC50 Values

The cloning of the cDNA for the human MCH receptor, preparation of arecombinant HEK293 cell line which expresses the human MCH receptor, andfunctional measurements with the recombinant cell line took place inanalogy to the description by Audinot et al. (J. Biol. Chem. 276, 13554-13 562, 2001). A difference from the reference was, however, the useof the plasmid pEAK8 from EDGE Biosystems (USA) to construct theexpression vector. The host used for the transfection was a transformedHEK cell line named “PEAK Stable Cells” (likewise from EDGE Biosystems).The functional measurements of the cellular calcium flux after additionof agonist (MCH) in the presence of ligand of the invention took placewith the aid of the FLIPR apparatus from Molecular Devices (USA) usingthe protocols of the apparatus manufacturer.

Biological Activity Testing

The IC50 values measured for exemplary compounds 33, 96 and 97 under theaforementioned conditions were of the order of from 0.01 to 10 μM.

General Explanations

a) Mode of Drawing the Structural Formulae

Only non-H atoms are depicted for clarity in the structural formulae ofthe given examples. Carbon atoms are not written out as “C”.

b) Salt Forms

Many of the compounds of the invention are bases and can form salts withappropriately strong acids. In particular, after purification of thecompounds by HPLC chromatography using a trifluoroacetic acid-containingmobile phase they may be in the form of hydrotrifluoroacetates. Thesecan be converted into the free bases shown by simple treatment of asolution of the salts for example with sodium carbonate solution.

c) Units of the Characterizing Data

The unit of the stated molecular weights is “g/mol”. Peaks observed inthe mass spectrum are indicated as integral quotient of the molarmolecular ion mass and the charge of the molecular ion (m/z).

Abbreviations

Unless indicated otherwise, the abbreviations in the examples below havethe following meaning:

-   NaBH₃CN=sodium cyanoborohydride-   DMF=N,N-dimethylformamide-   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   THF=tetrahydrofuran-   DMSO=dimethyl sulfoxide-   HOBt=1-hydroxybenzotriazole-   HOAt=1-hydroxy-7-azabenzotriazole-   HCl=hydrochloric acid-   HPLC=high performance liquid chromatography-   PyBOP=benzotriazol-1-yloxytris(pyrrolidino)phosphonium    hexafluorophosphate-   TOTU=O[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   eq=equivalents

EXAMPLE 1(1-{4-[5-(4-Butoxyphenyl)-[1,3,4]oxadiazol-2-yl]phenyl}pyrrolidin-3-yl)dimethylamine

Method A

A mixture of 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (100 mg),4-butoxy-benzoic acid (78 mg), 2-chloro-1,3-dimethyl-2-imidazoliumhexafluorophosphate (112 mg), N,N-diisopropylethylamine (0.14 ml) anddichloromethane (5 ml) was stirred for 12 hours. Volatiles were removed,and the residue was purified by preparative HPLC. The product with themolecular weight of 406.53 (C24H30N4O2) was obtained in this way; MS(ESI): 407 (M+H+).

4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide

A mixture of ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate (2.0 g),hydrazine hydrate (3.8 g) and ethanol (7 ml) was boiled under reflux for15 hours. After cooling to 5° C., the resulting precipitate was filteredoff with suction. The product with the molecular weight of 248.33(C13H20N4O) was obtained in this way; MS (ESI): 249 (M+H+).

Ethyl 4-(3-dimethylaminopyrrolidin-1-yl)benzoate

A mixture of ethyl 4-fluorobenzoate (4.47 g),dimethylpyrrolidin-3-ylamine (3.04 g), potassium carbonate (3.68 g) anddimethyl sulfoxide (20 ml) was heated at 130° C. for 7 hours. Aftercooling, the mixture was diluted with water and extracted with methyltert-butyl ether. The organic phase was washed with water, dried overmagnesium sulfate, filtered and concentrated. The product with themolecular weight of 262.35 (C15H22N2O2) was obtained in this way; MS(ESI): 263 (M+H+).

EXAMPLE 2Dimethyl-(1-{4-[5-(2-phenoxyethylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]phenyl}-pyrrolidin-3-yl)amine

4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide was reacted with(2-phenoxy-ethylsulfanyl)acetic acid by Method A. The product with themolecular weight of 424.57 (C23H28N4O2S) was obtained in this way; MS(ESI): 425 (M+H+).

EXAMPLE 3Dimethyl-(1-{4-[5-(4-phenoxyphenyl)[1,3,4]oxadiazol-2-yl]phenyl}pyrrolidin-3-yl)amine

Method B

A mixture ofN′-[4-(3-dimethylaminopyrrolidin-1-yl)benzoyl]-4-phenoxybenzohydrazide(178 mg), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess'reagent) (96 mg) and 5 ml of toluene was stirred at 60° C. for 1 h.After the reaction was complete, the reaction mixture was filtered, andthe filtrate was washed twice with ethyl acetate. The combined organicphases were subsequently washed with 5% strength sodium carbonatesolution and then dried over Chromabond XTR. Volatiles were removed andthe residue was purified by preparative HPLC. The product with themolecular weight of 426.21 (C26H26N4O2) was obtained in this way; MS(ESI): 427.21 (M+H+).

N′-[4-(3-Dimethylaminopyrrolidin-1-yl)benzoyl]4-phenoxybenzohydrazide

A mixture of 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (100 mg),4-phenoxybenzoic acid (77.5 mg), 1-propanephosphonic anhydride 50% indichloromethane (256 mg), N,N-diisopropylethylamine (0.208 ml) and DMF(3 ml) was stirred at room temperature for 72 h. The reaction mixturewas then filtered, washed twice with ethyl acetate and shaken with 0.5NNaOH. Volatiles were removed and the residue was purified by preparativeHPLC. The product with the molecular weight of 444.54 was obtained inthis way; MS (ESI): 445.24 (M+H+).

4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide was prepared asdescribed in method A, with 1 eq of Burgess' reagent being added onceagain in some cases after heating for 1 h in the cyclization step, andthen heating at 60° C. being continued for 1 hour.

Compounds 4-93 in table 1 were synthesized by method B.

MW MW Ex. Structure Molecular formula calc. measured 4

C27H28N4O2 440.22 441.24 5

C26H34N4O2 434.27 435.28 6

C27H28N4O2 440.22 441.27 7

C26H30N4O2 430.24 431.27 8

C27H34N4O2 446.27 447.27 9

C27H32N4O2 444.25 445.26 10

C22H26N4O 362.21 363.22 11

C23H26N4O3 406.20 407.22 12

C22H23N5O2 389.19 390.16 13

C27H28N4O2 440.22 441.23 14

C28H30N4O3 470.23 471.21 15

C28H30N4O2 454.24 455.25 16

C26H26N4O2 426.21 427.29 17

C27H28N4O2 440.22 441.23 18

C27H28N4O 425.23 425.24 19

C27H26N4O2 438.21 439.28 20

C24H23ClN4O2 434.15 436.02 21

C26H32N4O 416.26 417.36 22

C24H30N4O3 422.23 424.02 23

C27H28N4O2 440.22 441.27 24

C22H26N4O3 394.20 395.21 25

C28H30N4O3 470.23 471.25 26

C29H29N5O2 479.23 480.39 27

C22H23F3N4O3 448.17 449.22 28

C22H28N4OS 396.20 397.22 29

C25H25ClN4O3S2 528.11 530.08 30

C25H25ClN4O2 448.17 449.22 31

C25H38N4O 410.31 411.32 32

C23H28N4O2 392.22 393.24 33

C24H30N4O2 406.24 407.25 34

C23H28N4O3S 440.19 441.20 35

C26H29BrN6O 520.16 521.16 36

C25H27N5O2 429.22 430.23 37

C24H27BrN6O2 510.14 512.13 38

C26H32N4O3 448.25 449.26 39

C25H23F3N4O2 468.18 469.21 40

C25H25N5O4 459.19 460.21 41

C25H22ClF3N4O2 502.14 503.18 42

C25H30N4O3 434.23 435.24 43

C25H29N5OS 447.21 448.21 44

C28H28N6O 464.23 465.27 45

C32H33N5OS 535.24 536.25 46

C26H26N4O 410.21 411.23 47

C28H30N4O 438.24 439.27 48

C29H29N5O 463.24 464.26 49

C25H30N4O2 418.24 419.24 50

C25H29N5O2 431.23 432.25 51

C24H30N4OS 422.21 423.23 52

C24H29FN4O 408.23 409.24 53

C22H26N4O2S 410.18 411.21 54

C25H30N4O 402.24 403.26 55

C28H30N4O2 454.24 455.25 56

C28H29N5O2 467.23 468.27 57

C23H27ClN4OS 442.16 443.17 58

C26H26N4O3S 474.17 475.19 59

C28H29N5O2 467.27 468.27 60

C24H26N6O 414.22 415.23 61

C24H25N5OS 431.18 432.19 62

C27H25N5O 435.21 436.23 63

C26H24N4O2 424.19 425.22 64

C24H23FN4OS 434.16 435.19 65

C25H29FN4O2 436.23 437.26 66

C27H27FN4O 442.22 443.24 67

C27H31FN4O2 462.24 464.36 68

C25H25ClN4O3 464.16 465.18 69

C24H24N4O3 416.19 417.20 70

C23H23F3N4O2 444.18 445.20 71

C23H23N5O 385.19 386.22 72

C28H29FN4O 456.23 457.25 73

C26H29FN4O2 448.23 449.24 74

C22H23F3N4OS 448.15 449.16 75

C24H24ClN5OS 465.14 466.15 76

C25H25ClN4O2 448.17 449.20 77

C24H36N4O 396.29 397.31 78

C29H30N4O2 466.24 467.27 79

C25H32N4O3 436.25 437.27 80

C24H25ClN6O 448.18 449.21 81

C27H25F3N4O2 494.19 495.22 82

C26H25FN4O 428.20 429.23 83

C23H25F3N4O 430.20 431.20 84

C25H25ClN4O2S 480.14 481.17 85

C25H22BrF3N4O2 546.09 547.11 86

C24H22C1N5O4 479.14 480.15 87

C27H28N4O 424.23 425.24 88

C25H32N4O2 420.25 421.26 89

C27H28N4O 424.23 425.24 90

C23H25F3N4O2 446.19 447.19 91

C23H25N5OS 419.18 420.11 92

C26H28N4O2 428.22 429.24

EXAMPLE 93Dimethyl-(1-{4-[5-(4-phenoxybutyl)[1,3,4]oxadiazol-2-yl]phenyl}pyrrolidin-3-yl)amine

PyBOP (25.2 mg) was added to a mixture of 4-phenoxybutanohydrazide (10mg), 4-(3-dimethylaminopyrrolidin-1-yl)benzoic acid (12.1 mg), HOAt (6.6mg), triethylamine (13.5 μl) and DMF (0.15 ml) at 0° C. The mixture wasstirred at 0° C. for 10 min and then at room temperature for 3 h. Ethylacetate and water were then added to the reaction solution. The organicphase was subsequently washed twice each with 10% strength citric acidsolution, saturated sodium bicarbonate solution and water and dried oversodium sulfate, and the solvent was removed in vacuo.

The residue was then taken up in THF (0.4 ml), and EDC (6.1 mg) andtriethylamine (5.5 μl) were added, and the mixture was stirred at 50° C.for 16 h. Ethyl acetate and water were then added to the reactionsolution. The organic phase subsequently washed twice each with 10%strength citric acid solution, saturated sodium bicarbonate solution andwater and dried over sodium sulfate, and the solvent removed in vacuo.The residue was purified by preparative HPLC. The product with themolecular weight of 406.53 (C24H30N4O2) was obtained in this way; MS(ESI): 407.15 (M+H+).

4-Phenoxybutanohydrazide

A mixture of phenol (100 mg), ethyl 5-bromovalerate (222.2 mg), cesiumcarbonate (693 mg) and DMF (1.6 ml) was stirred at room temperature for12 h. Ethyl acetate and water were then added to the reaction solution,and the aqueous phase was adjusted to pH 6 with 2N HCl solution. Theaqueous phase extracted twice more with ethyl acetate. The combinedorganic phases were then washed with water and dried over sodiumsulfate, and the solvent was removed in vacuo. The product obtained inthis way was taken up in abs. ethanol (0.5 ml), 37.3 μl of hydrazinehydrate were added, and the mixture was heated under reflux for 12 h.Ethyl acetate and water were then added to the reaction solution, andthe aqueous phase was neutralized with 2N HCl solution. The aqueousphase was extracted twice with ethyl acetate. The combined organicphases were then washed with water and dried over sodium sulfate, andthe solvent was removed in vacuo. The residue was purified bypreparative HPLC. The product with the molecular weight of 208.11(C11H16ClN₂O2) was obtained in this way; MS (ESI): 209.1 (M+H+).

4-(3-Dimethylaminopyrrolidin-1-yl)benzoic Acid

A 1M sodium cyanoborohydride solution (1.32 ml) was added to a mixtureof methyl 4-(3-aminopyrrolidin-1-yl)benzoate (300 mg), acetic acid (81μl), formaldehyde (0.113 ml) and THF (3 ml). The reaction was stirred atroom temperature for 1 h, then the solvent was removed in vacuo, and theresidue was taken up again in ethyl acetate/water. The organic phase waswashed with water and dried over sodium sulfate, and the solvent wasremoved in vacuo.

The product obtained in this way was dissolved in a THF/water mixture(1:1) (3.1 ml), and potassium hydroxide (66.2 mg) was added. Thereaction was heated at 70° C. for 4 h. Ethyl acetate and water were thenadded to the reaction solution, and the aqueous phase was acidified with2N HCl solution. The aqueous phase was extracted twice with ethylacetate. The combined organic phases were then washed with water anddried over sodium sulfate, and the solvent was removed in vacuo. Theproduct with the molecular weight of 234.17 (C13H18N2O2) was obtained inthis way; MS (ESI): 235.10 (M+H+).

Methyl 4-(3-aminopyrrolidin-1-yl)benzoate

A mixture of 3-(tert-butoxycarbonylamino)pyrrolidine (1 g), methyl4-fluorobenzoate (0.83 ml), cesium carbonate (1.7 g) and DMF (10 ml) washeated at 100° C. for 12 h. Ethyl acetate and water were then added tothe reaction solution. The organic phase was then washed twice withwater and dried over sodium sulfate, and the solvent was removed invacuo.

The product obtained in this way was dissolved in methylene chloride (12ml), trifluoroacetic acid (6 ml) was added, and the mixture was stirredat room temperature for 90 min. The solvent was removed in vacuo, andthe residue was purified by preparative HPLC. The product with themolecular weight of 220.12 (C12H16N2O2) was obtained in this way; MS(ESI): 221.10 (M+H+).

EXAMPLE 94(1-{4-[5-(4-Butoxyphenyl)-[1,3,4]thiadiazol-2-yl]phenyl}pyrrolidin-3-yl)dimethylamine

A mixture ofN′-(4-butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide(100 mg), Lawesson's reagent (191 mg) and toluene (5 ml) was boiledunder reflux for 4 hours. Volatiles were removed, and the residue waspurified by preparative HPLC. The product with the molecular weight of422.60 (C24H30N4OS) was obtained in this way; MS (ESI): 423 (M+H+).

N′-(4-Butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide

A mixture of 4-butoxybenzoic acid (156 mg) and DMF (10 ml) was mixedwith TOTU (264 mg) and N,N-diisopropylethylamine (104 mg). After 10minutes, 4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (200 mg) wasadded. After one hour, the mixture was diluted with water and extractedwith ethyl acetate. The organic phase was washed with water, dried overmagnesium sulfate, filtered and concentrated. The product with themolecular weight of 424.55 (C24H32N4O3) was obtained in this way; MS(ESI): 425 (M+H+).

EXAMPLE 95((R)-3-{4-[5-(4-Chlorophenoxymethyl)[1,2,4]oxadiazol-3-yl]phenyl}cyclopentyl)-methylamine

PyBOP (558 mg), HOAt (146 mg) and triethylamine (0.299 ml) were added toa mixture of tert-butyl{(R)-1-[4-(N-hydroxycarbamimidoyl)phenyl]pyrrolidin-3-yl}methylcarbamate(358.5 mg), (4-chlorophenoxy)acetic acid (200 mg) and 3 ml of DMF at 0°C., and the reaction mixture was stirred at this temperature for 10 min.It was then stirred at room temperature for 2 h and ethyl acetate andwater were added to the reaction solution. The organic phase was thenwashed twice each with 10% strength citric acid solution, saturatedsodium bicarbonate solution and water, dried over sodium sulfate andfiltered, and the solvent was removed in vacuo.

The residue was then taken up in 10 ml of THF, and EDC (160 mg) andtriethylamine (0.144 ml) were added, and the mixture was stirred at 50°C. for 16 h. Ethyl acetate and water were then added to the reactionsolution. The organic phase was then washed twice each with 10% strengthcitric acid solution, saturated sodium bicarbonate solution and water,dried over sodium sulfate and filtered, and the solvent was removed invacuo.

The crude product was taken up in methylene chloride (7.2 ml), andtrifluoroacetic acid (1.8 ml) was added. The reaction was stirred atroom temperature for 5 h and then the solvent was removed in vacuo. Theresidue was purified by preparative HPLC. The product with the molecularweight of 384.14 (C20H21ClN₄O₂) was obtained in this way; MS(ESI):385.26 (M+H+).

(4-Chlorophenoxy)acetic Acid

A mixture of 4-chlorophenol (500 mg), methyl bromoacetate (0.368 ml),cesium carbonate (1.9 g) and 5 ml of acetone was stirred at roomtemperature for 12 h. Ethyl acetate and water were then added to thereaction solution, and the organic phase was washed twice with water,dried over sodium sulfate and filtered, and the solvent was removed invacuo. The crude product was dissolved in a 1:1 THF/water mixture (10ml), and potassium hydroxide (417 mg) was added. The reaction wasstirred at room temperature for 12 h. Ethyl acetate and water were thenadded to the reaction solution, and the aqueous phase was adjusted to pH2 and extracted several times with ethyl acetate. The combined organicphases were washed twice with water, dried over sodium sulfate andfiltered, and the solvent was removed in vacuo. The product with themolecular weight of 186.6 (C8H7ClO3) was obtained in this way; MS (ESI):227.0 (M+CH3CN).

{(R)-1-[4-(N-Hydroxycarbamimidoyl)phenyl]pyrrolidin-3-yl}methylcarbamicAcid Tert-Butyl Ester

Sodium hydride (253.4 mg) was added in portions to a solution oftert-butyl [(R)-1-(4-cyanophenyl)pyrrolidin-3-yl]carbamate (1.06 g) in12 ml of DMF at 0° C. After removal of the ice bath, methyl iodide(0.498 ml) was added dropwise to the reaction solution, which wasstirred at room temperature for 4 h. Ethyl acetate and water were thenadded to the reaction solution, and the organic phase was washed twicewith water, dried over sodium sulfate and filtered, and the solvent wasremoved in vacuo.

The crude product was dissolved in abs. ethanol (12 ml), andhydroxylamine (0.687 ml) was added. The reaction solution was heatedunder reflux for 12 h. Ethyl acetate and water were then added to thereaction solution, and the organic phase was washed twice with water anddried over sodium sulfate, and the solvent was removed in vacuo. Theresidue was purified by preparative HPLC. The product with the molecularweight of 334.42 (C17H26N4O3) was obtained in this way; MS (ESI): 335.20(M+H+).

[(R)-1-(4-Cyanophenyl)pyrrolidin-3-yl]carbamic Acid

A mixture of (3R)-(+)-(tert-butoxycarbonylaminopyrrolidine (1.0 g),p-fluorobenzonitrile (650 mg), cesium carbonate (1.75 g) and 5 ml of DMFwas stirred at 50° C. for 12 h. Ethyl acetate and water were then addedto the reaction solution, and the organic phase was washed twice withwater, dried over sodium sulfate and filtered, and the solvent wasremoved in vacuo. The residue was purified by preparative HPLC. Theproduct with the molecular weight of 287.36 (C16H21N3O2) was obtained inthis way; MS (ESI): 288.20 (M+H+).

EXAMPLE 96((R)-1-{4-[5-(4-Chlorobenzyloxymethyl)[1,2,4]oxadiazol-3-yl]phenyl}pyrrolidin-3-yl)methylamine

A solution of (4-chlorobenzyloxy)acetic acid (70 mg) in thionyl chloride(1 ml) was stirred at room temperature for 1 h, and then toluene wasadded and the solvent was stripped off in vacuo. This procedure wasrepeated twice more. The acid chloride was then taken up in methylenechloride (1.4 ml),{(R)-1-[4-(N-hydroxycarbamimidoyl)phenyl]pyrrolidin-3-yl}methylcarbamicacid tert-butyl ester (116.7 mg), triethylamine (0.05 ml) were added,and the mixture was stirred at room temperature for 12 h. The volatilecomponents were removed in vacuo, and the residue was taken up in ethylacetate/water. The organic phase was washed twice with water and driedover sodium sulfate, and the solvent was removed in vacuo. The residuewas purified by preparative HPLC. The product with the molecular weightof 398.15 (C21H23ClN4O2) was obtained in this way; MS (ESI): 399.41(M+H+).

(4-Chlorobenzyloxy)acetic acid was prepared in analogy to(4-chlorophenoxy)-acetic acid using 4-chlorobenzyl bromide as precursor.The product with the molecular weight of 200.62 (C9H9ClO3) was obtainedin this way; MS (ESI): 222.95 (M+Na—H).

EXAMPLE 974-Chloro-N-{3-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl][1,2,4]oxadiazol-5-ylmethyl}benzamide

Method C

TOTU (51.4 mg) and N,N-diisopropylethylamine (0.05 ml) were added to amixture of{1-[4-(5-aminomethyl[1,2,4]oxadiazol-3-yl)phenyl]pyrrolidin-3-yl}dimethylamine(75.3 mg), 4-chlorobenzoic acid (23.5 mg) and DMF (0.96 ml), and thesolution was stirred at room temperature for 12 h. The crude product waspurified by preparative HPLC (RP) and then purified again bychromatography on silica gel (dichloromethane/MeOH/AcOH/H₂O=90/10/1/1).The product with the molecular weight of 425.16 (C22H24ClN5O2) wasobtained in this way; MS (ESI): 426.17 (M+H).

{1-[4-(5-Aminomethyl[1,2,4]oxadiazol-3-yl)phenyl]pyrrolidin-3-yl}dimethylamine

PyBOP (546.4 mg), HOAt (136.1 mg) and triethylamine (0.279 ml) wereadded to a mixture of4-(3-dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine (248.3 mg),tert-butoxycarbonylaminoacetic acid (175.2 mg) and DMF (2.8 ml) at 0° C.and the mixture was stirred at this temperature for 10 min. It wassubsequently stirred at room temperature for 2 h and then ethyl acetateand water were added to the reaction solution. The organic phase thenwashed twice each with 10% strength citric acid solution, saturatedsodium bicarbonate solution and water, dried over sodium sulfate andfiltered, and the solvent removed in vacuo. The residue was then takenup in 6.2 ml of THF, and EDC (105 mg) and triethylamine (0.09 ml) wereadded, and the mixture was stirred at 50° C. for 16 h. Ethyl acetate andwater were then added to the reaction solution. The organic phase thenwashed twice each with 10% strength citric acid solution, saturatedsodium bicarbonate solution and water and dried over sodium sulfate, andthe solvent removed in vacuo. The crude product was taken up inmethylene chloride (9.6 ml), and trifluoroacetic acid (2.3 ml) wasadded. The reaction was stirred at room temperature for 5 h and then thesolvent was removed in vacuo. The residue was purified by preparativeHPLC. The product with the molecular weight of 287.37 (C₁₅H₂₁N₅₀) wasobtained in this way; MS (ESI): 288.05 (M+H+).

4-(3-Dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine

A mixture of 3-(dimethylamino)pyrrolidine (1.1 g), p-fluorobenzonitrile(1.2 g), potassium carbonate (2.8 g) and acetonitrile (15 ml) wasstirred at 80° C. for 12 h. The reaction solution was then filtered, andthe precipitate was washed with acetonitrile, the solvent was removed invacuo, and the residue was taken up again in ethyl acetate. The ethylacetate phase was washed twice with water and then dried over sodiumsulfate, and the solvent was removed in vacuo. The product obtained inthis way was dissolved in abs. ethanol (48.7 ml), and hydroxylamine (1.4ml) was added to the solution. The reaction mixture was heated underreflux for 12 h. The precipitate obtained after cooling the reactionsolution was filtered off and washed with a little ethanol.

The product with the molecular weight of 248.33 (C13H20N4O) was obtainedin this way; MS (ESI): 249.15 (M+H+).

Examples 98-110 in table 2 were synthesized by method C.

MW MW Ex. Structure Molecular formula calc. measured 98

C23H26ClN5O2 439.18 440.19 99

C23H26ClN5O3 455.17 456.17 100

C22H23ClFN5O2 443,15 444.21 101

C22H25N5O2 391.20 392.25 102

C22H23ClFN5O2 443.15 444.21 103

C22H24FN5O2 409.19 410.22 104

C21H24N6O2 392.20 393.24 105

C21H23ClN6O2 426.16 427.19 106

C21H24N6O2 392.20 393.25 107

C21H23ClN6O2 426.16 427.20 108

C21H24N6O2 392.20 393.26 109

C21H31N5O2 385.25 386.27 110

C23H33N5O2 411.26 412.30

EXAMPLE 111[1-(4-{5-[(4-Chlorobenzylamino)methyl][1,2,4]oxadiazol-3-yl}phenyl)pyrrolidin-3-yl]-dimethylamine

Method D

Polymer-bound sodium cyanoborohydride (5 eq) was added to a mixture of{1-[4-(5-aminomethyl[1,2,4]oxadiazol-3-yl)phenyl]pyrrolidin-3-yl}dimethylamine(40.1 mg), 4-chlorobenzaldehyde (42.2 mg), acetic acid (17.2 μl),triethylamine (27.9 μl) and THF (1 ml), and the reaction mixture wasstirred at room temperature for 12 h. The polymer-bound reagent wasfiltered off and the solvent was removed in vacuo. The residue waspurified by preparative HPLC. The product with the molecular weight of411.18 (C22H26ClN5O) was obtained in this way; MS (ESI): 412.23 (M+H+).

EXAMPLE 112[1-(4-{5-[(4-Methoxybenzylamino)methyl][1,2,4]oxadiazol-3-yl}phenyl)pyrrolidin-3-y]dimethylamine

{1-[4-(5-aminomethyl[1,2,4]oxadiazol-3-yl)phenyl)pyrrolidin-3-yl}dimethylaminewas reacted with p-anisaldehyde by method D. The product with themolecular weight of 407.23 (C23H29N5O2) was obtained in this way; MS(ESI): 408.30 (M+H+).

EXAMPLE 113(1-{4-[5-(4-Fluorobenzyloxymethyl)[1,2,4]oxadiazol-3-yl]phenyl}pyrrolidin-3-yl)dimethylamine

4-Fluorobenzyl bromide (18.9 mg) and potassium carbonate (27.6 mg) wereadded to a mixture of{3-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl][1,2,4]oxadiazol-5-yl}methanol(28.8 mg) and DMF (0.3 ml). The reaction mixture was stirred at 60° C.for 3 h, filtered and purified by preparative HPLC. The product with themolecular weight of 396.20 (C22H25FN4O2) was obtained in this way; MS(ESI): 397.27 (M+H+).

{3-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl][1,2,4]oxadiazol-5-yl}methanol

-   PyBOP (546.4 mg), HOAt (136.1 mg) and triethylamine (0.139 ml) were    added to a mixture of    4-(3-dimethylaminopyrrolidin-1-yl)-N-hydroxybenzamidine (248.3 mg),    benzyloxyacetic acid (0.143 ml) and DMF (3.0 ml) at 0° C., and the    mixture was stirred at this temperature for 10 min. It was    subsequently stirred at room temperature for 1 h, and then ethyl    acetate and water were added to the reaction solution. The organic    phase was then washed twice each with 10% strength citric acid    solution, saturated sodium bicarbonate solution and water and dried    over sodium sulfate, and the solvent was removed in vacuo.

The residue was then taken up in 3 ml of THF, and EDC (170.8 mg) andtriethylamine (0.139 ml) were added, and the mixture was stirred at 80°C. for 16 h. Ethyl acetate and water were then added to the reactionsolution. The organic phase was then washed twice each with 10% strengthcitric acid solution, saturated sodium bicarbonate solution and waterand dried over sodium sulfate, and the solvent was removed in vacuo.

The residue was dissolved in methylene chloride (4.4 ml), and thesolution was cooled to −78° C. At this temperature, a 1M borontrichloride solution (3 ml) was added. The reaction was allowed to warmto room temperature overnight, and then ethyl acetate and water wereadded. The product with the molecular weight of 288.2 (C15H20N4O2) wasobtained in this way; MS (ESI): 289.2 (M+H+).

The following examples could be synthesized analogously:

A

B

C

D

E

F

G

H

I

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

AB

AC

AD

AE

AF

AG

AH

AI

1. A compound of the formula I,

in which the meanings are R1, R2 independently of one another H,(C₁-C₈)-alkyl, —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(s)O(R21); or R1 and R2form together with the nitrogen atom to which they are bonded a 4 to10-membered mono-, bi- or spirocyclic ring which, apart from thenitrogen atom, may include 0 to 4 additional heteroatoms selected fromthe group of oxygen, nitrogen and sulfur, where the heterocyclic ringsystem may additionally be substituted by F, Cl, Br, CF₃, NO₂, CN,(C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R22),CON(R23)(R24), hydroxy, COO(R25), N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28) orSO₂CH₃; o 0, 1, 2, 3, 4, 5, 6; q, s independently of one another 0, 1,2, 3, 4; R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26,R27, R28 independently of one another H, (C₁-C₆)-alkyl; R17 and R18, R23and R24, R27 and R28 independently of one another optionally togetherwith the nitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also include 0-1 furtherheteroatoms from the group of NH, N—(C1-C6)-alkyl, oxygen and sulfur;R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33), 3-12membered mono-, bi- or spirocyclic ring which may comprise one or moreheteroatoms from the group of N, O and S, and the 3-12 membered ring maycomprise further substituents such as F, Cl, Br, I, OH, CF₃, NO₂, CN,OCF₃, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,(C₂-C₆)-alkynyl, O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl,N(R34)(R35), CO(C₁-C₆)-alkyl, COO(R36) and S(O)_(u) (R37); u 0, 1, 2;R34, R35 independently of one another H, (C₁-C₈)-alkyl; R34 and R35optionally together with the nitrogen atom to which they are bonded a5-6 membered ring which, apart from the nitrogen atom, may also include0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl, oxygenand sulfur, and optionally be substituted by 1-2 oxo groups; R36, R37 H,(C₁-C₈)-alkyl; R13, R14 independently of one another H, (C₁-C₈)-alkyl,hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; R29, R30, R31independently of one another H, (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl,(C₀-C₈)-alkylene-aryl; R32, R33 independently of one another H,(C₁-C₆)-alkyl or R32 and R33 optionally together with the nitrogen atomto which they are bonded a 5-6 membered ring which, apart from thenitrogen atom, may also include 0-1 further heteroatoms from the groupof NH, N—(C₁-C₆)-alkyl, oxygen and sulfur and optionally be substitutedby 1-2 oxo groups; R3 H, (C₁-C₆)-alkyl; R4, R5 independently of oneanother H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl,S—(C₁-C₆)-alkyl; R6, R7, R8, R9 independently of one another H,(C₁-C₈)-alkyl, or R6 and R7, R8 and R9 independently of one anotheroptionally oxo; n, m 1; A, B, D, G C(R38); R38 H, F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,(C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl,N(R39)(R40), SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, CON(R41)(R42),N(R43)CO(R44), N(R45)SO₂(R46), CO(R47), —(CR48R49)_(x)—O(R50); R39, R40,R41, R42, R43, R45 independently of one another H, (C₁-C₈)-alkyl; or R39and R40, R41 and R42 independently of one another optionally togetherwith the nitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also include 0-1 furtherheteroatoms from the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;R44, R46, R47 independently of one another H, (C₁-C₈)-alkyl, aryl; R48,R49 independently of one another H, (C₁-C₈)-alkyl; R50 H, (C₁-C₆)-alkyl;x 1, 2, 3, 4; Het 1,3,4-oxadiazolyl; X a bond, a group of the formula—(CR51R52)_(y)— in which one or more —(CR51R52)— groups may be replacedby Y C═C, C≡C; Y O, S, N(R53), CO, SO, SO₂; R51, R52 independently ofone another H, (C₁-C₄)-alkyl, where R51 and R52 in the y groups may ineach case have the same or different meanings; y 1, 2, 3, 4, 5, 6; R53H, (C₁-C₈)-alkyl; E 3-14 membered bivalent carbo- or heterocyclic ringstructure having 0-4 heteroatoms from the group of N, O and S, which mayoptionally have substituents from the group of H, F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, oxo, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,O—(C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl,O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R54)(R55), SO₂—CH₃, COOH,COO—(C₁-C₆)-alkyl, CON(R56)(R57), N(R58)CO(R59), N(R60)SO₂(R61), CO(R62)and be mono- or bicyclic; R54, R55, R56, R57, R58, R60 independently ofone another H, (C₁-C₈)-alkyl; R54 and R55, R56 and R57 independently ofone another optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogen atom, may alsoinclude 0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,oxygen and sulfur; R59, R61, R62 independently of one another H,(C₁-C₈)-alkyl, aryl; K a bond, a group of the formula —(CR63R64)_(z)— inwhich one or more —(CR63R64)-groups may be replaced by Z, C≡C, C═C; Z O,S, N(R65), CO, SO, SO₂; R63, R64 independently of one another H,(C₁-C₈)-alkyl, hydroxy, (C₁-C₆)-alkoxy, where R63 and R64 in the zgroups may in each case have the same or different meanings; z 1, 2, 3,4, 5, 6; R65 H, (C₁-C₈)-alkyl; R11 H, (C₁-C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, a 3 to10-membered mono-, bi- or spirocyclic ring which may include 0 to 4heteroatoms selected from the group of oxygen, nitrogen and sulfur,where the ring system may additionally be substituted by F, Cl, Br, CF₃,NO₂, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₀-C₈)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68), hydroxy,hydroxy-(C₁-C₄)-alkyl, COO(R69), N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72) orSO₂CH₃; R66, R67, R68, R69, R70, R71, R72 independently of one anotherH, (C₁-C₈)-alkyl; or R67 and R68, R71 and R72 independently of oneanother optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogen atom, may alsoinclude 0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,oxygen and sulfur; or the N-oxides thereof and the physiologicallytolerated salts thereof.
 2. A compound of the formula I as claimed inclaim 1, in which the meanings are R1, R2 independently of one anotherH, (C₁-C₈)-alkyl, —(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)_(o)—R12,CO(C(R15)(R16))_(q)N(R17)(R18), CO(C(R19)(R20))_(s)O(R21); or R1 and R2form together with the nitrogen atom to which they are bonded a 4 to10-membered mono-, bi- or spirocyclic ring which, apart from thenitrogen atom, may include 0 to 4 additional heteroatoms selected fromthe group of oxygen, nitrogen and sulfur, where the heterocyclic ringsystem may additionally be substituted by F, Cl, Br, CF₃, NO₂, CN,(C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl, (C₀-C₈)-alkylene-aryl, oxo, CO(R22),CON(R23)(R24), hydroxy, COO(R25), N(R26)CO(C₁-C₆)-alkyl or N(R27)(R28);R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), N(R32)(R33), 3-12membered mono-, bi- or spirocyclic ring which may comprise one or moreheteroatoms from the group of N, O and S, and the 3-12 membered ring maycomprise further substituents such as F, Cl, Br, I, OH, CF₃, NO₂, CN,OCF₃, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,(C₂-C₆)-alkynyl, O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl,N(R34)(R35), CO(C₁-C₆)-alkyl and COO(R36); and R6, R7, R8, R9independently of one another H, (C₁-C₈)-alkyl; where the remainingvariables for formula I are as defined in claim
 1. 3. A compound of theformula I as claimed in claim 1, in which the meanings are R1, R2independently of one another H, (C₁-C₈)-alkyl, —(CR13R14)_(o)—R12,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₃-C₈)-alkenyl, CO—(C₁-C₈)-alkyl,—CO—(CH₂)_(o)—R12, CO(C(R15)(R16))_(q)N(R17)(R18),CO(C(R19)(R20))_(s)O(R21); or R1 and R2 form together with the nitrogenatom to which they are bonded a 4 to 10-membered mono-, bi- orspirocyclic ring which, apart from the nitrogen atom, may include 0 to 2additional heteroatoms selected from the group of oxygen, nitrogen andsulfur, where the heterocyclic ring system may additionally besubstituted by F, Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,(C₀-C₂)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy, COO(R25),N(R26)CO(C₁-C₆)-alkyl, N(R27)(R28) or SO₂CH₃; o 0, 1, 2, 3, 4, 5, 6; q1, 2, 3; s 0, 1, 2, 3, 4; R15, R16, R17, R18, R19, R20, R21, R22, R23,R24, R25, R26, R27, R28 independently of one another H, (C₁-C₆)-alkyl;or R17 and R18, R23 and R24, R27 and R28 independently of one anotheroptionally together with the nitrogen atom to which they are bonded a5-6 membered ring which, apart from the nitrogen atom, may also include0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl, oxygenand sulfur; R12 OH, O—(C₁-C₆)-alkyl, CN, COO(R29), CON(R30)(R31), 3-12membered mono-, bi- or spirocyclic ring which may comprise one or moreheteroatoms from the group of N, O and S, and the 3-12 membered ring maycomprise further substituents such as F, Cl, Br, OH, CF₃, CN, oxo,O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, (C₁-C₆)-alkyl,O—(C₀-C₈)-alkylene-aryl, (C₀-C₈)-alkylene-aryl, N(R34)(R35),CO(C₁-C₆)-alkyl, COO(R36), S(O)_(u)(R37); u 0, 1, 2; R34, R35independently of one another H, (C₁-C₈)-alkyl; or R34 and R35 optionallytogether with the nitrogen atom to which they are bonded a 5-6 memberedring which, apart from the nitrogen atom, may also include 0-1 furtherheteroatoms from the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur,and optionally be substituted by 1-2 oxo groups; R36, R37 H,(C₁-C₈)-alkyl; R13, R14 independently of one another H, (C₁-C₈)-alkyl,hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; R29, R30, R31independently of one another H, (C₁-C₈)-alkyl; R3 H, (C₁-C₆)-alkyl; R4,R5 independently of one another H, (C₁-C₆)-alkyl, OH, O—(C₁-C₆)-alkyl,O—CO(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl; R6, R7, R8, R9 H; or R6 and R7, R8and R9 independently of one another optionally oxo; n 1; m 1; A, B, D, GC(R38); or the groups A and B or D and G are in each case C(R38) andtogether form an ortho-phenylene unit so that the overall result is a1,4-bisubstituted naphthalene system; R38 H, F, Cl, Br, CF₃, CN,O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl,N(R39)(R40), SO₂—CH₃, CON(R41)(R42), N(R43)CO(R44), CO(R47),—(CR48R49)_(x)—O(R50); R39, R40, R41, R42, R43 independently of oneanother H, (C₁-C₈)-alkyl; or R39 and R40, R41 and R42 independently ofone another optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogen atom, may alsoinclude 0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,oxygen and sulfur; R44, R47 independently of one another H,(C₁-C₈)-alkyl, aryl; R48, R49 H; R50 H, (C₁-C₆)-alkyl; x 1, 2; Het is

in which A′ is O, X′, Y′ are; X a bond, a group of the formula—(CR51R52)_(y)—, in which one or more —(CR51R52)-groups may be replacedby Y, C═C, C≡C; R51, R52 independently of one another H, (C₁-C₄)-alkyl,where R51 and R52 in the y groups may in each case have the same ordifferent meanings; Y O, S, N(R53), CO; R53 H, (C₁-C₈)-alkyl; E 3-8membered bivalent carbo- or heterocyclic ring structure having 0-4heteroatoms from the group of N, O and S, which may optionally havesubstituents from the group of H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, O—(C₃-C₈)-cycloalkyl, (C₂-C₆)-alkynyl,(C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R54)(R55),SO₂—CH₃, N(R58)CO(R59), N(R60)SO₂(R61), CO(R62) and be mono- orbicyclic; R54, R55, R58, R60 independently of one another H,(C₁-C₈)-alkyl; R59, R61, R62 independently of one another H,(C₁-C₈)-alkyl, aryl; K O, a bond, CH₂O, OCH₂, S, SO, SO₂, N(R80),N(R81)CO, CON(R82), (C(R83)(R84))_(v), CO, C═C, C≡C, SCH₂, SO₂CH₂; v 1,2, 3, 4; R80, R81, R82, R83, R84 independently of one another H,(C₁-C₈)-alkyl; R11 H, (C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₃-C₈)-alkenyl, (C₃-C₈)-alkynyl, a 3 to 10-membered mono-, bi- orspirocyclic ring which may include 0 to 4 heteroatoms selected from thegroup of oxygen, nitrogen and sulfur, where the ring system mayadditionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,O—(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,(C₀-C₈)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68), hydroxy, COO(R69),N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72) or SO₂CH₃; R66, R67, R68, R69, R70,R71, R72 independently of one another H, (C₁-C₈)-alkyl; or R67 and R68,R71 and R72 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ring which, apartfrom the nitrogen atom, may also include 0-1 further heteroatoms fromthe group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur; or the N-oxidesthereof and the physiologically tolerated salts thereof.
 4. A compoundof the formula I as claimed in claim 1 or 3, in which the meanings are:R1, R2 independently of one another H, (C₁-C₈)-alkyl,—(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, CO—(C₁-C₈)-alkyl,—CO—(CH₂)_(o)—R12, CO(C(R15)(R16))_(q)N(R17)(R18),CO(C(R19)(R20))_(o)O(R21); or R1 and R2 form together with the nitrogenatom to which they are bonded a 4 to 10-membered mono- or bicyclic ringwhich, apart from the nitrogen atom, may include 0 to 2 additionalheteroatoms selected from the group of oxygen, nitrogen and sulfur,where the heterocyclic ring system may additionally be substituted by F,Cl, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₀-C₂)-alkylene-aryl, oxo, CO(R22), hydroxy, N(R27)(R28) or SO₂CH₃; o0, 1, 2, 3, 4; q 1 or 2; s 0, 1, 2, 3; R15, R16, R17, R18, R19, R20,R21, R22, R27, R28 independently of one another H, (C₁-C₆)-alkyl; or R17and R18, R27 and R28 independently of one another optionally togetherwith the nitrogen atom to which they are bonded a 5-6 membered ringselected from pyrrolidine, piperidine, N-methylpiperazine andmorpholine; R12 OH, O—(C₁-C₆)-alkyl, CN, 3-10 membered mono- or bicyclicring which may comprise 1-3 heteroatoms from the group of N, O and S,and the 3-10 membered ring may comprise further substituents such as F,Cl, Br, OH, CF₃, CN, oxo, O—(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,(C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl, N(R34)(R35), CO(C₁-C₆)-alkyl; u 0or 2; R34, R35 independently of one another H, (C₁-C₈)-alkyl; or R34 andR35 optionally together with the nitrogen atom to which they are bondeda 5-6 membered ring which, apart from the nitrogen atom, may alsoinclude 0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,oxygen and sulfur, and optionally be substituted by 1-2 oxo groups; R36,R37 H, (C₁-C₈)-alkyl; R13, R14 independently of one another H,(C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;R3 H; R4, R5 independently of one another H, (C₁-C₆)-alkyl, OH,O—(C₁-C₆)-alkyl, O—CO(C₁-C₆)-alkyl; R6, R7, R8, R9 H; n 1 m 1; A, B, D,G C(R38); R38 H, F, Cl, Br, CF₃, CN, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,SO₂—CH₃, CON(R41)(R42), N(R43)CO(R44), CO(R47), —(CR48R49)_(x)—O(R50);R41, R42, R43 independently of one another H, (C₁-C₈)-alkyl; or R39 andR40, R41 and R42 independently of one another optionally together withthe nitrogen atom to which they are bonded a 5-6 membered ring which,apart from the nitrogen atom, may also include 0-1 further heteroatomsfrom the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur; R47 H,(C₁-C₈)-alkyl; R48, R49 H; R50 H, (C₁-C₆)-alkyl; x 1; Het1,3,4-oxadiazolyl; X a bond, CH₂—CH₂, CH₂Y, YCH₂, (R75)YCH₂,CH₂—NCO(R75), CH₂CON(R75); C(R76)(R77), C(R78)(R79)O, N(R75), C═C, C≡C;Y O, S, N(R53); R53 H, (C₁-C₈)-alkyl; R75, R76, R77, R78, R79independently of one another H, (C₁-C₈)-alkyl; E 5-7 membered bivalentcarbo- or heterocyclic ring structure having 0-3 heteroatoms from thegroup of N, O and S, which may optionally have substituents from thegroup of H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,O—(C₀-C₈)-alkylene-aryl, S-aryl, N(R54)(R55), SO₂—CH₃, N(R58)CO(R59),CO(R62) and be mono- or bicyclic; R54, R55, R58 independently of oneanother H, (C₁-C₈)-alkyl; R59, R62 independently of one another H,(C₁-C₈)-alkyl; K O, a bond, CH₂O, OCH₂, N(R80), N(R81)CO, CON(R82),(C(R83)(R84))_(v), CO, C≡C, SCH₂; v 1, 2, 3; R80, R81, R83, R84independently of one another H, (C₁-C₈)-alkyl; R11 (C₁-C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono-, bi- orspirocyclic ring which may include 0 to 3 heteroatoms selected from thegroup of oxygen, nitrogen and sulfur, where the ring system mayadditionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,O—(C₁-C₈)-alkyl, (C₀-C₂)-alkylene-aryl, oxo, CO(R66), CON(R67)(R68),hydroxy, N(R70)CO(C₁-C₆)-alkyl, N(R71)(R72) or SO₂CH₃; R66, R67, R68,R70, R71, R72 independently of one another H, (C₁-C₈)-alkyl; or R67 andR68, R71 and R72 independently of one another optionally together withthe nitrogen atom to which they are bonded a 5-6 membered ring which,apart from the nitrogen atom, may also include 0-1 further heteroatomsfrom the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur; or theN-oxides thereof and the physiologically tolerated salts thereof.
 5. Acompound of the formula I as claimed in claim 1, 2 or 3, in whichradicals R1, R2, R11, R38 and the groups X, E and K have the followingmeanings: R1, R2 independently of one another H, (C₁-C₈)-alkyl,—(CR13R14)_(o)—R12, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, or R1 and R2 formtogether with the nitrogen atom to which they are bonded a 4 to10-membered mono-, bi- or spirocyclic ring which, apart from thenitrogen atom, may include 0 to 2 additional heteroatoms selected fromthe group of oxygen, nitrogen and sulfur, where the heterocyclic ringsystem may additionally be substituted by (C₁-C₆)-alkyl,O—(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl,(C₀-C₂)-alkylene-aryl, oxo, CO(R22), CON(R23)(R24), hydroxy, N(R27)(R28)or SO₂CH₃; o 0, 1, 2, 3, 4; R22, R23, R24, R27, R28 independently of oneanother H, (C₁-C₆)-alkyl; or R23 and R24, R27 and R28 independently ofone another optionally together with the nitrogen atom to which they arebonded a 5-6 membered ring which, apart from the nitrogen atom, may alsoinclude 0-1 further heteroatoms from the group of NH, N—(C₁-C₆)-alkyl,oxygen and sulfur; R12 OH, O—(C₁-C₆)-alkyl, CN 3-12 membered mono-, bi-or spirocyclic ring which may comprise 1 to 3 heteroatoms from the groupof N, O and S, and the 3-12 membered ring may comprise furthersubstituents such as F, OH, CF₃, CN, oxo, (C₁-C₆)-alkyl,(C₀-C₂)-alkylene-aryl, N(R34)(R35), COO(R36), CO(C₁-C₆)-alkyl; R34, R35independently of one another H, (C₁-C₄)-alkyl; R36 H, (C₁-C₆)-alkyl,(C₀-C₂)-alkylene-aryl; R13, R14 independently of one another H,(C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl;R38 H, F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl; X a bond, CH₂CH₂, C(R76)(R77),N(R75), C═C, (R75)YCH₂, CH₂—NCO(R75), CH₂CON(R75); Y O, S, N(R53), COR75, R76, R77 independently of one another H, (C₁-C₈)-alkyl; R53 H,(C₁-C₈)-alkyl; E 5-7 membered bivalent carbo- or heterocyclic ringstructure having 0-3 heteroatoms from the group of N, O and S, which mayoptionally have substituents from the group of H, F, Cl, Br, CF₃, OH,CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SO₂—CH₃, CO(R65); R65 H,(C₁-C₈)-alkyl; K O, a bond, CH₂O, CH₂, OCH₂, S, SO₂, N(R80), N(R81)CO,CON(R82), (C(R83)(R84))_(v), CO, C≡C, SCH₂, SO₂CH₂; v 1, 2, 3; R80, R81,R82, R83, R84 independently of one another H, (C₁-C₈)-alkyl; R11(C₁-C₈)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono-,bi- or spirocyclic ring which may include 0 to 4 heteroatoms selectedfrom the group of oxygen, nitrogen and sulfur, where the ring system mayadditionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,O—(C₁-C₈)-alkyl, oxo, CO(R66), hydroxy, N(R70)CO(C₁-C₆)-alkyl, orSO₂CH₃; R66, R70 independently of one another H, (C₁-C₈)-alkyl; theN-oxides thereof and the physiologically tolerated salts thereof.
 6. Amedicament comprising one or more of the compounds as claimed inclaim
 1. 7. A medicament comprising one or more of the compounds asclaimed in claim 1 and one or more anorectic active ingredients.
 8. Aprocess for producing a medicament comprising one or more of thecompounds of the formula I as claimed in claim 1, which comprises mixingthe active ingredient with a pharmaceutically suitable carrier, andconverting this mixture into a form suitable for administration.
 9. Acompound of the formula I as claimed in claim 4, in which the meaningsare: R1, R2independently of one another H, (C₁-C₈)-alkyl,—(CR13R14)₀—R12, (C₁-C₄)-alkyl, CO—(C₁-C₈)-alkyl, —CO—(CH₂)₀—R12,CO(C(R15)(R16))_(q)N(R17)(R18), or R1 and R2 form together with thenitrogen atom to which they are bonded a 4 to 10-membered mono- orbicyclic ring which, apart from the nitrogen atom, may include 0 to 2additional heteroatoms selected from the group of oxygen and nitrogen,where the heterocyclic ring system may additionally he substituted by F,(C₁-C₆)-alkyl, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, oxo, CO(R22), hydroxy,N(R27)(R28); o 0, 1, 2, 3; q 1 or 2; s 0, 1, 2; R15, R16, R17, R18, R19,R20, R21, R22, R27, R28 independently of one another H, (C₁-C₆)-alkyl;or R17 and R18, R27and R28 independently of one another optionallytogether with the nitrogen atom to which they are bonded a 5-6 memberedring selected from pyrrolidine, piperidine, N-methylpiperazine andmorpholine; R12 OH, O—(C₁-C₆)-alkyl, 3-10 membered mono- or bicyclicring which may comprise 1-2 hetero atoms from the group of N, O and S,and the 3-10 membered ring may comprise further substituents such as F,OH, oxo, (C₁-C₆)-alkyl, CO(C₁-C₆)-alkyl; u 2; R34, R35 independently ofone another H, (C₁-C₅)-alkyl; or R34 and R35 optionally together withthe nitrogen atom to which they are bonded a 5-6 membered ring which,apart from the nitrogen atom, may also include 0-1 further heteroatomsfrom the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur, and optionallybe substituted by 1-2 oxo groups; R36, R37 H, (C₁-C₈)-alkyl; R13, R14independently of one another H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl,OH, (C₁-C₄)-alkoxy-(C₁-C₄)-alkyl; R3 H; R4, R5 independently of oneanother H, OH, O—(C₁-C₆)-alkyl; R6, R7, R8, R9 H; n 1 m 1; A,B,D,GC(R38); R38 H, F, Cl, CF₃, CN, (C₁-C₆)-alkyl, —(CR48R49)_(x)—O(R50);R41, R42, R43 independently of one another 1-I, (C₁-C₈)-alkyl; or R39and R40, R41 and R42 independently of one another optionally togetherwith the nitrogen atom to which they are bonded a 5-6 membered ringwhich, apart from the nitrogen atom, may also include 0-1 furtherheteroatoms from the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur;R47 H, (C₁-C₈)-alkyl; R48, R49 H; R50 H, (C₁-C₆)-alkyl; x 1; Het1,3,4-oxadiazolyl; X a bond, CH₂—CH₂, C(R76)(R77), N(R75), CH₂Y,CH₂Y(R75), CH₂—NCO(R75), CH₂—CON(R75); C═C; Y O, S, N(R53); R53 H,(C₁-C₈)-alkyl; R75, R76, R77, R78, R79 independently of one another H,(C₁-C₈)-alkyl; E 5-7 membered bivalent carbo- or heterocyclic ringstructure having 0-2 heteroatoms from the group of N, O and S, which mayoptionally have substituents from the group of H, F, CI, Br, OH, CF₃,NO₂, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, N(R54)(R55),SO₂—CH₃, CO(R62), and which is monocyclic; R54, R55, R58 independentlyof one another H, (C₁-C₈)-alkyl; R59, R62 independently of one anotherH, (C₁-C₈)-alkyl; K O, a bond, CH₂O₁ OCH₂, CON(R82), (C(R83)(R84))_(v),CO, C≡C; v 1, 2; R80, R81, R83, R84 independently of one another H,(C₁-C₈)-alkyl; R11 preferably (C₁C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono- or bicyclic ringwhich may include 0 to 2 heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the ring system may additionally besubstituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl, O—(C₁-C₈)-alkyl, oxo,CO(R66), CON(R67)(R68), N(R70)CO(C₁-C₆)-alkyl, or SO₂CH₃; R66, R67, R68,R70, R71, R72 independently of one another H, (C₁ -C₈)-alkyl; or R67 andR68, R71 and R72 independently of one another optionally together withthe nitrogen atom to which they are bonded a 5-6 membered ring which,apart from the nitrogen atom, may also include 0-1 further heteroatomsfrom the group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur; or theN-oxides thereof and the physiologically tolerated salts thereof.
 10. Acompound of the formula I as claimed in claim 5, in which radicals R1,R2, R11, R38 and the groups X, E and K have the following meanings: R1,R2 independently of one another H, (C₁-C₈)-alkyl, or R1 and R2 formtogether with the nitrogen atom to which they are bonded a 5 to6-menibered monocyclic ring which, apart from the nitrogen atom, mayinclude 0 to 1 additional heteroatoms selected from the group of oxygen,nitrogen and sulfur, where the heterocyclic ring system may additionallybe substituted by (C₁-C₆)-alkyl; o 0, 1, 2, 3, 4; R22, R23, R24, R27,R28 independently of one another H, (C₁-C₆)-alkyl; or R23 and R24, R27and R28 independently of one another optionally together with thenitrogen atom to which they are bonded a 5-6 membered ring which, apartfrom the nitrogen atom, may also include 0-1 further heteroatoms fromthe group of NH, N—(C₁-C₆)-alkyl, oxygen and sulfur; R12 OH,O—(C₁-C₆)-alkyl, CN 3-12 membered mono-, bi- or spirocyclic ring whichmay comprise 1 to 3 heteroatoms from the group of N, O and S, and the3-12 membered ring may comprise further substituents such as F, OH, CF₃,CN, oxo, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl, N(R34)(R35), COO(R36),CO(C₁-C₆)-alkyl; R34, R35 independently of one another H, (C₁-C₄)-alkyl;R36 H, (C₁-C₆)-alkyl, (C₀-C₂)-alkylene-aryl; R13, R14 independently ofone another H, (C₁-C₈)-alkyl, hydroxy-(C₁-C₄)-alkyl, OH, (C₁-C₄-alkoxy-(C₁-C₄)-alkyl; R38 H, F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl; X abond, CH₂CH₂, C(R76)(R77), N(R75), C═C, (R75)YCH₂, CH₂—NCO(R75),CH₂CON(R75); Y O, S, N(R53), CO R75, R76, R77 independently of oneanother H, (C₁-C₈)-alkyl; R53 H, (C₁-C₈)-alkyl; E 5-7 membered bivalentcarbo- or heterocyclic ring structure having 0-3 heteroatoms from thegroup of N, O and S, which may optionally have substituents from thegroup of H, F, Cl, Br, CF₃, OH, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, SO₂—CH₃, CO(R65); R65 H, (C₁-C₈)-alkyl; K O, a bond,CH₂O, CH₂, OCH₂, N(R80), C≡C; v 1, 2, 3; R80, R81, R82, R83, R84independently of one another H, (C₁-C₈)-alkyl; R11 (C₁-C₈)-alkyl,(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, a 3 to 10-membered mono-, bi- orspirocyclic ring which may include 0 to 4 heteroatoins selected from thegroup of oxygen, nitrogen and sulfur, where the ring system mayadditionally be substituted by F, Cl, Br, CF₃, CN, (C₁-C₆)-alkyl,O—(C₁-C₆)-alkyl, oxo, CO(R66), hydroxy, N(R70)CO(C₁-C₆)-alkyl, orSO₂CH₃; R66, R70 independently of one another H, (C₁-C₈)-alkyl; theN-oxides thereof and the physiologically tolerated salts thereof.
 11. Amethod of treating obesity comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I asclaimed in claim 1 or a pharmaceutically acceptable salt thereof.
 12. Amethod of treating type II diabetes comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula I as claimed in claim 1 or a pharmaceutically acceptable saltthereof.